CYP2B6

Gene Summary

Gene:CYP2B6; cytochrome P450 family 2 subfamily B member 6
Aliases: CPB6, EFVM, IIB1, P450, CYP2B, CYP2B7, CYP2B7P, CYPIIB6
Location:19q13.2
Summary:This gene, CYP2B6, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by phenobarbital. The enzyme is known to metabolize some xenobiotics, such as the anti-cancer drugs cyclophosphamide and ifosphamide. Transcript variants for this gene have been described; however, it has not been resolved whether these transcripts are in fact produced by this gene or by a closely related pseudogene, CYP2B7. Both the gene and the pseudogene are located in the middle of a CYP2A pseudogene found in a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cytochrome P450 2B6
Source:NCBIAccessed: 11 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Single Nucleotide Polymorphism
  • Biotransformation
  • Oligonucleotide Array Sequence Analysis
  • Young Adult
  • Case-Control Studies
  • Genotype
  • Transfection
  • Cytochrome P-450 CYP2B6
  • Drug Resistance
  • Gene Expression Profiling
  • Liver Cancer
  • Polymorphism
  • Alleles
  • Enzymologic Gene Expression Regulation
  • Cytochrome P-450 CYP2C9
  • Antineoplastic Agents, Alkylating
  • Adjuvant Chemotherapy
  • Cancer DNA
  • Tamoxifen
  • Cytochrome P-450 CYP2C19
  • Glutathione Transferase
  • Childhood Cancer
  • Biomarkers, Tumor
  • Cancer Gene Expression Regulation
  • Risk Factors
  • Adolescents
  • CYP2D6
  • Cohort Studies
  • Cytochrome P-450 CYP3A
  • Doxorubicin
  • Transplantation Conditioning
  • Cytochrome P-450 Enzyme System
  • Genetic Predisposition
  • Antineoplastic Agents
  • Aryl Hydrocarbon Hydroxylases
  • RTPCR
  • Promoter Regions
  • Chromosome 19
  • Xenobiotics
  • Breast Cancer
  • Cyclophosphamide
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CYP2B6 (cancer-related)

Murphy SE
Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6.
Chem Res Toxicol. 2017; 30(1):410-419 [PubMed] Related Publications
Nicotine is the primary addictive agent in tobacco, and P450 2A6 (gene name: CYP2A6) is the primary catalyst of nicotine metabolism. It was proposed more than 20 years ago that individuals who metabolize nicotine poorly would smoke less, either fewer cigarettes per day or less intensely per cigarette, compared to smokers who metabolize nicotine more efficiently. These poor metabolizers would then be less likely to develop lung cancer due to their lower exposure to the many carcinogens delivered with nicotine in each puff of smoke. Numerous studies have reported that smokers who carry reduced activity or null CYP2A6 alleles do smoke less. Yet only in Asian populations, both Japanese and Chinese, which have a high prevalence of genetic variants, has a link between CYP2A6, smoking dose, and lung cancer been established. In other ethnic groups, it has been challenging to confirm a direct link between P450 2A6-mediated nicotine metabolism and the risk of lung cancer. This challenge is due in part to the difficulty in accurately quantifying smoking dose and accurately predicting or measuring P450 2A6-mediated nicotine metabolism. Biomarkers of nicotine metabolism and smoking exposure, including the ratio of trans-3-hydroxycotine to cotinine, a measure of P450 2A6 activity and plasma cotinine, or urinary total nicotine equivalents (the sum of nicotine and six metabolites) as measures of exposure are useful for addressing this challenge. However, to take full advantage of these biomarkers in the study of ethnic/racial differences in the risk of lung cancer requires the complete characterization of nicotine metabolism across ethnic/racial groups. Variation in metabolism pathways, other than those catalyzed by P450 2A6, can impact biomarkers of both nicotine metabolism and dose. This is clearly important for smokers with low levels of UGT2B10-catalyzed nicotine and cotinine glucuronidation because the UGT2B10 genotype influences plasma cotinine levels. Cotinine is not glucuronidated in 15% of African American smokers (compared to 1% of Whites) due to the prevalence of a UGT2B10 splice variant. This variant contributes significantly to the higher plasma cotinine levels per cigarette in this group and may also influence the accuracy of the 3HCOT to cotinine ratio as a measure of P450 2A6 activity.

Tsuji D, Ikeda M, Yamamoto K, et al.
Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.
Medicine (Baltimore). 2016; 95(44):e5151 [PubMed] Related Publications
Chemotherapy-induced neutropenia (CIN) is one of the major adverse events that necessitate chemotherapy dose reduction. This study aimed to evaluate the association between grade 4 neutropenia and genetic polymorphisms in breast cancer patients. In this genetic polymorphism association study, peripheral blood samples from 100 consecutive breast cancer outpatients, between August 2012 and September 2014, treated with doxorubicin and cyclophosphamide (AC) combination chemotherapy were genotyped for polymorphisms in adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), cytochrome P450 (CYP) enzyme-coding genes (CYP2B6 and CYP3A5), glutathione S-transferase (GST), and excision repair cross-complementing 1 (ERCC1). Associations between grade 4 neutropenia and genotypes as well as risk factors were examined using multivariate logistic regression. From 100 patients, 32.0% had grade 4 neutropenia. Multivariate logistic regression analysis revealed that ERCC1 118C > T (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.22-9.69; P = 0.020), CYP2B6*6 (OR, 4.51; 95% CI, 1.21-16.95; P = 0.025), body mass index (BMI) (OR, 6.94; 95% CI, 1.15-41.67; P = 0.035), and baseline white blood cell (WBC) count (OR, 2.99; 95% CI, 1.06-8.40; P = 0.038) were significant predictors of grade 4 neutropenia. ERCC1 and CYP2B6 gene polymorphisms were associated with the extent of grade 4 neutropenia in patients receiving AC chemotherapy. In addition to previously known risk factors, BMI and WBC counts, ERCC1 and CYP2B6 gene polymorphisms were also identified as independent strong predictors of grade 4 neutropenia.

Yamazaki H
Differences in Toxicological and Pharmacological Responses Mediated by Polymorphic Cytochromes P450 and Related Drug-Metabolizing Enzymes.
Chem Res Toxicol. 2017; 30(1):53-60 [PubMed] Related Publications
Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used. Interindividual variability of P450-dependent drug clearances in cynomolgus monkeys and common marmosets is partly accounted for by polymorphic P450 variants and/or aging, just as it is in humans with increased prevalence of polypharmacy. Genotyping of P450 genes in nonhuman primates would be beneficial before and/or after drug metabolism and toxicity testing and evaluation as well in humans. Genome-wide association studies in humans have been rapidly advanced; however, unique whole-gene deletion of P450 2A6 was subsequently developed to cover nicotine-related lung cancer risk study. Regarding polypharmacy, toxicological research should generally be aimed at identifying the risk of adverse drug events following specific potential drug exposures by examining single or multiple metabolic pathways involving single or multiple drug-metabolizing enzymes. Current and next-generation research of drug metabolism and disposition resulting in drug toxicity would be addressed under advanced knowledge of polymorphic and age-related intra- and/or interspecies differences of drug-metabolizing enzymes. In the near future, humanized animal models combining transplanted hepatocytes and a humanized immune system may be available to study human immune reactions caused by human-type drug metabolites. Such sophisticated models should provide preclinical predictions of human drug metabolism and potential toxicity.

Karakurt S
Modulatory effects of rutin on the expression of cytochrome P450s and antioxidant enzymes in human hepatoma cells.
Acta Pharm. 2016; 66(4):491-502 [PubMed] Related Publications
Expression of a drug and xenobiotic metabolizing enzymes, cytochrome P450s (CYPs), and antioxidant enzymes can be modulated by various factors. The flavonoid rutin was investigated for its anti-carcinogen and protective effects as well as modulatory action on CYPs and phase II enzymes in human hepatocellular carcinoma cells. Rutin inhibited proliferation of HEPG2 cells in a dose-dependent manner with the IC50 value of 52.7 μmol L-1 and invasion of HEPG2 cells (21.6 %, p = 0.0018) and colony formation of those invaded cells (57.4 %, p < 0.0001). Rutin treatment also significantly increased early/late-stage apoptosis in HEPG2 cells (28.9 %, p < 0.001). Treatment by rutin significantly inhibited protein expressions of cytochrome P450-dependent CYP3A4 (75.3 %, p < 0.0001), elevated CYP1A1 enzymes (1.7-fold, p = 0.0084) and increased protein expressions of antioxidant and phase II reaction catalyzing enzymes, NQO1 (2.42-fold, p < 0.0001) and GSTP1 (2.03-fold, p < 0.0001). Besides, rutin treatment significantly inhibited mRNA expression of CYP3A4 (73.2 %, p=0.0014). Also, CYP1A1, NQO1 and GSTP1 mRNA expressions were significantly increased 2.77-fold (p = 0.029), 4.85- fold (p = 0.0051) and 9.84-fold (p < 0.0001), respectively.

Kakino K, Kiyohara C, Horiuchi T, Nakanishi Y
CYP2E1 rs2031920, COMT rs4680 Polymorphisms, Cigarette Smoking, Alcohol Use and Lung Cancer Risk in a Japanese Population.
Asian Pac J Cancer Prev. 2016; 17(8):4063-70 [PubMed] Related Publications
BACKGROUND: Cytochrome P450 2E1 (CYP2E1) and catechol-O-methyltransferase (COMT) genes may contribute to susceptibility to lung cancer because of their critical involvement in mechanisms of carcinogenesis.
MATERIALS AND METHODS: We evaluated the role of CYP2E1 rs2031920 and COMT rs4680 in a case-control study involving 462 lung cancer cases and 379 controls in Japanese. Logistic regression was used to assess adjusted odds ratios (OR) and 95% confidence intervals (CI). Multiplicative and additive interactions with cigarette smoking or alcohol use were also examined.
RESULTS: Neither CYP2E1 rs2031920 nor COMT rs4680 was associated with lung cancer risk overall. However, smokers with the CC genotype of CYP2E1 rs2031920 (OR = 3.57, 95% CI = 2.26-5.63) presented a higher risk of lung cancer than those with at least one T allele (OR = 2.91, 95% CI = 1.70-4.98) as compared to never-smokers with at least one T allele (reference). Subjects with excessive drinking and the CC genotype of CYP2E1 rs2031920 had a significantly higher risk (OR=2.22, 95% CI =1.39-3.56) than appropriate drinkers with at least one T allele. A similar tendency was observed between COMT rs4680 and either smoking or drinking habits. There were no multiplicative or additive interactions between the polymorphisms and either smoking or alcohol use.
CONCLUSIONS: Our findings indicate that CYP2E1 rs2031920 and COMT rs4680 are not major contributors to lung cancer risk in our Japanese population. Future studies on the genetics of lung cancer in Japanese and their environment interactions are required.

Ibrahim MH, Rashed RA, Hassan NM, et al.
ssociation of Cytochrome P450-1B1 Gene Polymorphisms with Risk of Breast Cancer: an Egyptian Study.
Asian Pac J Cancer Prev. 2016; 17(6):2861-6 [PubMed] Related Publications
It is thought that population characteristics of breast cancer may be due to a variation in the frequency of different alleles of genes such as CYP1B1. We aimed to determine the association of CYP1B1 polymorphisms in 200 breast cancer cases and 40 controls by PCR-RFLP. Frequencies were assessed with clinical and risk factors in Egyptian patients. The genotype LV and the Leu allele frequencies for patients and controls were 42.9% and 50%, and 52.9% and 53.3%, respectively), with no significant differences observed (P values = 0.8 and 0.6, respectively). There was also no significant association between genotypes and any risk factors for cases (>0.05) except laterality and metastasis of the tumor (P values=0.006 and 0.06, respectively). The CYP1B1 polymorphism Val432Leu was not associated with breast cancer in Egypt, but may provide clues for future studies into early detection of the disease.

Salimi S, Sajadian M, Khodamian M, et al.
Combination effect of cytochrome P450 1A1 gene polymorphisms on uterine leiomyoma: A case-control study.
Bosn J Basic Med Sci. 2016; 16(3):209-14 [PubMed] Free Access to Full Article Related Publications
Uterine leiomyoma (UL) is an estrogen-dependent neoplasm of the uterus, and estrogen metabolizing enzymes affect its progression. This study aimed to evaluate the association between two single-nucleotide polymorphisms of cytochrome P450 1A1 (CYP1A1) gene and UL risk. The study consisted of 105 patients with UL and 112 healthy women as controls. Ile462Val (A/G) and Asp449Asp (T/C) polymorphisms of CYP1A1 gene were analyzed by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism methods, respectively. The findings indicated no association between Ile462Val (A/G) and Asp449Asp (T/C) polymorphisms of CYP1A1 gene and UL (p < 0.05). However, the combination effect of TT/AG genotypes of the Asp449Asp (T/C) and Ile462Val (A/G) polymorphisms was associated with 4.3-fold higher risk of UL. In addition, haplotype analysis revealed that TG haplotype of the Asp449Asp (T/C) and Ile462Val (A/G) polymorphisms could increase the UL risk nearly 4.9-fold. Asp449Asp (T/C) and Ile462Val (A/G) polymorphisms of CYP1A1 gene were not associated with UL susceptibility; however, the combination of the TT/AG genotypes and TG haplotype could increase the UL risk.

Ren J, He BZ, Zhang TS, et al.
Meta-analysis of correlation between the CYP1A2 -3860 G > A polymorphism and lung cancer risk.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
The aim of this meta-analysis was to assess the association between a polymorphism (-3860 G > A) in the cytochrome P450 1A2 (CYP1A2) gene and lung cancer susceptibility. Relevant studies were retrieved from the PubMed and EMBase databases, and additionally evaluated for conformance with the inclusion criteria. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) in all selected studies were used to assess the relationship between the CYP1A2 -3860 G > A polymorphism and lung cancer risk. The data was pooled using Stata v.11. Six studies, comprising 1168 lung cancer patients and 1598 controls, were included in this meta-analysis. We found no correlation between the CYP1A2 -3860 G > A polymorphism and lung cancer risk in any of the models (AA vs GG: OR = 4.79, 95%CI = 0.03-702.67; GA vs GG: OR = 1.33, 95%CI = 0.74-2.39; dominant model: OR = 1.41, 95%CI = 0.69-2.90; recessive model: OR = 4.07, 95%CI = 0.04-368.35). Moreover, we observed no statistically significant association between CYP1A2 -3860 G > A and lung cancer susceptibility when stratified by the ethnicity of the sample populations, sample size, and study quality, except in a low-quality study. Our findings indicated that the -3860 G > A polymorphism in CYP1A2 might not be a risk factor for lung cancer.

Xi XP, Zhuang J, Teng MJ, et al.
MicroRNA-17 induces epithelial-mesenchymal transition consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.
Int J Mol Med. 2016; 38(2):499-506 [PubMed] Related Publications
MicroRNA-17 (miRNA-17/miR‑17) expression has been confirmed to be significantly higher in colorectal cancer tissues than in normal tissues. However, its exact role in colorectal cancer has not yet been fully elucidated. In this study, we found that miR-17 not only promoted epithelial-mesenchymal transition (EMT), but also promoted the formation of a stem cell-like population in colon cancer DLD1 cells. We also wished to determine the role of cytochrome P450, family 7, subfamily B, polypeptide 1 (CYP7B1) in CRC. miR-17 was overexpressed using a recombinant plasmid and CYP7B1 was silenced by transfection with shRNA. Western blot analysis was used to determine protein expression in the DLD1 cells and in tumor tissues obtained from patients with colon cancer. Our results revealed that miR‑17 overexpression led to the degradation of CYP7B1 mRNA expression in DLD1 cells. In addition, we found that the silencing of CYB7B1 promoted EMT and the formation of a stem cell-like population in the cells. Thus, our findings demonstrate that miR‑17 induces EMT consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.

Abo-Hashem EM, El-Emshaty WM, Farag Rel S, et al.
Genetic Polymorphisms of Cytochrome P4501A1 (CYP1A1) and Glutathione S-Transferase P1 (GSTP1) and Risk of Hepatocellular Carcinoma Among Chronic Hepatitis C Patients in Egypt.
Biochem Genet. 2016; 54(5):696-713 [PubMed] Related Publications
Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase P1 (GSTP1) genes are involved in the metabolism of many carcinogens. Polymorphisms in these genes with altered enzyme activity have been reported. The present study evaluated the synergistic effect between CYP1A1 and GSTP1 gene polymorphisms and smoking on development of HCV-related liver disease and hepatocellular carcinoma (HCC). The patients group comprised 40 patients with HCC and 40 patients with liver cirrhosis. The control group comprised 40 healthy subjects having no history of malignancy. The genetic polymorphisms were studied using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) technique on blood samples. The number of current or former smoker among HCC and cirrhotic patients as well as the median Pack/year of cigarette smoked were significantly higher in HCC and liver cirrhotic patients than in control group. Subjects with CYP1A1 gene variants (m1 and m3) had no significant risk to develop cirrhosis or HCC compared to control group. Individuals carrying the Ile/Val genotype of GSTP1 had a significant increased risk of HCC (OR of 2.2, 95 % CI 1.143-4.261) and had larger tumor size. No significant risk was observed on combining both genes variants or on combining smoking with variants of both genes. In conclusion, the GSTP1 Ile/Val genotype and Val allele are associated with an increased risk of HCC. CYP1A1 and GSTP1 genes variants interaction did not increase the risk of HCC.

Šemeláková M, Jendželovský R, Fedoročko P
Drug membrane transporters and CYP3A4 are affected by hypericin, hyperforin or aristoforin in colon adenocarcinoma cells.
Biomed Pharmacother. 2016; 81:38-47 [PubMed] Related Publications
Our previous results have shown that the combination of hypericin-mediated photodynamic therapy (HY-PDT) at sub-optimal dose with hyperforin (HP) (compounds of Hypericum sp.), or its stable derivative aristoforin (AR) stimulates generation of reactive oxygen species (ROS) leading to antitumour activity. This enhanced oxidative stress evoked the need for an explanation for HY accumulation in colon cancer cells pretreated with HP or AR. Generally, the therapeutic efficacy of chemotherapeutics is limited by drug resistance related to the overexpression of drug efflux transporters in tumour cells. Therefore, the impact of non-activated hypericin (HY), HY-PDT, HP and AR on cell membrane transporter systems (Multidrug resistance-associated protein 1-MRP1/ABCC1, Multidrug resistance-associated protein 2-MRP2/ABCC2, Breast cancer resistance protein - BCRP/ABCG2, P-glycoprotein-P-gp/ABCC1) and cytochrome P450 3A4 (CYP3A4) was evaluated. The different effects of the three compounds on their expression, protein level and activity was determined under specific PDT light (T0+, T6+) or dark conditions (T0- T6-). We found that HP or AR treatment affected the protein levels of MRP2 and P-gp, whereas HP decreased MRP2 and P-gp expression mostly in the T0+ and T6+ conditions, while AR decreased MRP2 in T0- and T6+. Moreover, HY-PDT treatment induced the expression of MRP1. Our data demonstrate that HP or AR treatment in light or dark PDT conditions had an inhibitory effect on the activity of individual membrane transport proteins and significantly decreased CYP3A4 activity in HT-29 cells. We found that HP or AR significantly affected intracellular accumulation of HY in HT-29 colon adenocarcinoma cells. These results suggest that HY, HP and AR might affect the efficiency of anti-cancer drugs, through interaction with membrane transporters and CYP3A4.

Yamauchi K, Kokuryo T, Yokoyama Y, et al.
Prediction of Early Recurrence After Curative Resection of Colorectal Liver Metastasis and Subsequent S-1 Chemotherapy.
Anticancer Res. 2016; 36(5):2175-9 [PubMed] Related Publications
BACKGROUND: S-1, an oral 5-fluorouracil (5-FU)-based medicine that combines tegafur, gimeracil and oteracil potassium is commonly used as an adjuvant chemotherapeutic drug for the treatment of colorectal cancer.
PATIENTS AND METHODS: We enrolled 53 patients who underwent curative resection for colorectal cancer and liver metastasis (synchronous, n=24; metachronous, n=29). The subsequent adjuvant chemotherapy with oral S-1 administration was initiated within 56 days after liver resection. Recurrence was evaluated by imaging studies, that were performed during the first year after liver resection. Of the 53 patients, 25 who did not recur within 1 year were defined as being in the no-recurrence (NREC) group and the remaining 18 patients were defined as being in the early-recurrence (EREC) group. There were no significant differences in gene expression profiling for drug resistance and metabolism between the NREC group and the EREC group.
RESULTS: In synchronous liver metastasis, there was no significant difference in early recurrence between serum carcinoembryonic antigen (CEA) ≤5 ng/ml and serum CEA >5 ng/ml (8/24 vs. 16/24, respectively). In metachronous liver metastasis, the early recurrence rate was significantly higher in patients with CEA >5 ng/ml compared to patients with CEA ≤5 ng/ml (15/29 vs. 14/29, p=0.05). The expression of cytochrome P450 2C19 (CYP2C19) and ATP-binding cassette, sub-family B member 1 (ABCB1) were significantly lower in the EREC group (6/15) compared to the NREC group (9/15) in colorectal cancer with metachronous liver metastasis and with serum CEA >5 ng/ml.
CONCLUSION: Although the exact reason for down-regulation of these genes in the group with poor prognosis is unknown, the information obtained in this study may be useful in clinical practice for colorectal cancer.

Song J, Tao ZH, Liu XY, et al.
Relationship between CYP17 gene polymorphisms and risk of prostate cancer.
Genet Mol Res. 2016; 15(1):15017866 [PubMed] Related Publications
Cytochrome P450 17a-hydroxylase (CYP17) plays a critical role in androgen biosynthesis. Polymorphisms of the CYP17 promoter have been proposed as risk factors for prostate cancer; however, some studies have produced inconclusive or controversial results. We investigated the relationship between polymorphisms of the CYP17 gene and the risk of prostate cancer. A total of 176 patients with prostate cancer were enrolled in the study, and 168 healthy individuals acted as the control group. The participants were divided into those <71 years old and those ≥71 years old. Restriction fragment length polymorphism-polymerase chain reaction was used to confirm the genotype of CYP17 in the samples. The prostate-specific antigen (PSA) concentrations were also measured in all subjects. When T/C and C/C were compared with T/T, the ORs were 0.478 (P = 0.489) and 0.814 (P = 0.367), respectively. There was no significant difference in PSA concentration among the three genotypes in the <71 group, whereas there were statistically significant differences in the ≥71 group (P = 0.003 and 0.012, respectively). There was no significant difference in free PSA and total PSA levels between the three groups and the control group. The T/C and C/C genotypes were not associated with the risk of prostate cancer, and there were no significant differences between them. In the ≥71 group, the T/C and C/C genotypes were closely associated with prostate cancer, which suggests that the CYP17 gene might be a risk factor for prostate cancer in males of advanced age.

Zheng L, Li X, Meng X, et al.
Competing endogenous RNA networks of CYP4Z1 and pseudogene CYP4Z2P confer tamoxifen resistance in breast cancer.
Mol Cell Endocrinol. 2016; 427:133-42 [PubMed] Related Publications
Patients with estrogen receptor α (ERα)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3'UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3'UTR enhances the transcriptional activity of ERα through the activation of ERα phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3'UTRs increase ERα activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3'UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3'UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer.

Johnson N, De Ieso P, Migliorini G, et al.
Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.
Cancer Res. 2016; 76(6):1485-93 [PubMed] Free Access to Full Article Related Publications
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.

Bag A, Jyala NS, Bag N
Cytochrome P450 1A1 genetic polymorphisms as cancer biomarkers.
Indian J Cancer. 2015 Oct-Dec; 52(4):479-89 [PubMed] Related Publications
Phase I metabolic enzyme CYP1A1 plays an important role in xenobiotics metabolism and has been extensively studied as a cancer risk biomarker. CYP1A1 is polymorphic and its four variants, e.g., CYP1A1* 2 A, CYP1A1* 2C, CYP1A1* 3 and CYP1A1* 4 with trivial names m1, m2, m3, and m4 respectively, are most commonly studied for cancer link. Gene- gene interaction studies combining polymorphisms of this enzyme with those of phase II detoxifying enzymes, especially glutathione S- transferases (GSTs) revealed greater risk for cancer susceptibility. Variants of CYP1A1 have also been found to be associated with chemotherapeutic adverse- effects. Results of these studies, however, remained largely contradictory mainly because of lack of statistical power due to involvement of small sample size. Strongly powered experimental designs involving gene- gene, gene- environment interactions are required in order to validate CYP1A1 as reliable cancer- biomarker.

Ahmed NS, Elghazawy NH, ElHady AK, et al.
Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism.
Eur J Med Chem. 2016; 112:171-9 [PubMed] Related Publications
Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-α and ER-β receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI50) that was 1000 times more potent than that of TAM (GI50 < 0.005 μM vs 1.58 μM, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers.

Noll EM, Eisen C, Stenzinger A, et al.
CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.
Nat Med. 2016; 22(3):278-87 [PubMed] Free Access to Full Article Related Publications
Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

Munetsuna E, Kittaka A, Chen TC, Sakaki T
Metabolism and Action of 25-Hydroxy-19-nor-Vitamin D₃ in Human Prostate Cells.
Vitam Horm. 2016; 100:357-77 [PubMed] Related Publications
Since the discovery of 1α,25(OH)2D3 in the early 1970s, it has been widely accepted that this metabolite is responsible for the biological actions of vitamin D. Likewise, we have assumed that 25(OH)-19-nor-D3-dependent growth inhibition of human prostate PZ-HPV-7 cells was the result of its subsequent conversion to 1α,25(OH)2-19-nor-D3, catalyzed by CYP27B1 within the prostate cells. However, further in vitro studies in a reconstituted system using recombinant CYP27B1 revealed that 25(OH)-19-nor-D3 was hardly converted to 1α,25(OH)2-19-nor-D3 by the enzyme. The kinetic analysis of 1α-hydroxylation of 25(OH)D3 and 25(OH)-19-nor-D3 demonstrated that the k(cat)/K(m) for 25(OH)-19-nor-D3 is less than 0.1% of that for 25(OH)D3. When 25(OH)-19-nor-D3 was added to cultured PZ-HPV-7 cells, eight metabolites were detected, while no 1α,25(OH)2-19-nor-D3 was found. In addition, the time course of VDR translocation into the nucleus induced by 100 nM 25(OH)-19-nor-D3, and the subsequent transactivation of CYP24A1 gene were almost identical to those induced by 1 nM 1α,25(OH)2-19-nor-D3. These results strongly suggest that 25(OH)-19-nor-D3 binds directly to VDR as a ligand to transport VDR into the nucleus to induce CYP24A1 gene transactivation. Furthermore, knockdown of CYP27B1 gene did not affect the antiproliferative activity of 25(OH)-19-nor-D3, whereas VDR knockdown attenuated the effect, suggesting that the antiproliferative activity of 25(OH)-19-nor-D3 is VDR dependent but CYP27B1 independent. Finally, our recent studies using the same cell line demonstrate that 25(OH)D3 can act as a VDR agonist to induce gene transactivation. These findings suggest that vitamin D analogs without 1α-hydroxyl group could be developed as drugs for osteoporosis or cancer treatment.

Hedrich WD, Xiao J, Heyward S, et al.
Activation of the Constitutive Androstane Receptor Increases the Therapeutic Index of CHOP in Lymphoma Treatment.
Mol Cancer Ther. 2016; 15(3):392-401 [PubMed] Free Access to Full Article Related Publications
The constitutive androstane receptor (CAR and NR1i3) is a key regulator of CYP2B6, the enzyme predominantly responsible for the biotransformation of cyclophosphamide (CPA) to its pharmacologically active metabolite, 4-hydroxycyclophosphamide (4-OH-CPA). Previous studies from our laboratory illustrated that CAR activation increases the formation of 4-OH-CPA; however, CPA is rarely used clinically outside of combination therapies. Here, we hypothesize that including a selective human CAR activator with the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen can improve the efficacy without exacerbating off-target toxicity of this regimen in non-Hodgkin lymphoma treatment. In this study, we have developed a novel multiorgan coculture system containing human primary hepatocytes for hepatic metabolism, lymphoma cells as a model target for CHOP, and cardiomyocytes as a major site of off-target toxicity associated with this regimen. We found that a selective human CAR activator, CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime), altered expression of key drug-metabolizing enzymes and transporters in human hepatocytes, which positively affects the metabolic profile of CHOP. Coadministration of CITCO and CHOP in the coculture model led to significantly enhanced cytotoxicity in lymphoma cells but not in cardiomyocytes. Moreover, the beneficial effects of CITCO were abrogated when CAR knockout HepaRG cells were used in the coculture model. Importantly, synergistic anticancer effects were observed between CITCO and CHOP, in that inclusion of CITCO alongside the CHOP regimen offers comparable antineoplastic activity toward lymphoma cells at significantly reduced drug concentrations, and the decreased CHOP load attenuates cardiotoxicity. Overall, these findings provide a potentially promising novel strategy for facilitating CHOP-based chemotherapy.

Park SL, Tiirikainen MI, Patel YM, et al.
Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risks of lung cancer and effect on their smoking intensity.
Carcinogenesis. 2016; 37(3):269-79 [PubMed] Free Access to Full Article Related Publications
Genetic variation in cytochrome P450 2A6 (CYP2A6) gene is the primary contributor to the intraindividual and interindividual differences in nicotine metabolism and has been found to influence smoking intensity. However, no study has evaluated the relationship between CYP2A6 genetic variants and the CYP2A6 activity ratio (total 3-hydroxycotinine/cotinine) and their influence on smoking intensity [total nicotine equivalents (TNE)], across five racial/ethnic groups found to have disparate rates of lung cancer. This study genotyped 10 known functional CYP2A6 genetic or copy number variants in 2115 current smokers from the multiethnic cohort study [African Americans (AA) = 350, Native Hawaiians (NH) = 288, Whites = 413, Latinos (LA) = 437 and Japanese Americans (JA) = 627] to conduct such an investigation. Here, we found that LA had the highest CYP2A6 activity followed by Whites, AA, NH and JA, who had the lowest levels. Adjusting for age, sex, race/ethnicity and body mass index, we found that CYP2A6 diplotypes were predictive of TNE levels, particularly in AA and JA (P trend < 0.0001). However, only in JA did the association remain after accounting for cigarettes per day. Also, it is only in this population that the lower activity ratio supports lower TNE levels, carcinogen exposure and thereby lower risk of lung cancer. Despite the association between nicotine metabolism (CYP2A6 activity phenotype and diplotypes) and smoking intensity (TNE), CYP2A6 levels did not correlate with the higher TNE levels found in AA nor the lower TNE levels found in LA, suggesting that other factors may influence smoking dose in these populations. Therefore, further study in these populations is recommended.

Schmidt M, Scholz CJ, Polednik C, Roller J
Spheroid-based 3-dimensional culture models: Gene expression and functionality in head and neck cancer.
Oncol Rep. 2016; 35(4):2431-40 [PubMed] Related Publications
In the present study a panel of 12 head and neck cancer (HNSCC) cell lines were tested for spheroid formation. Since the size and morphology of spheroids is dependent on both cell adhesion and proliferation in the 3-dimensional (3D) context, morphology of HNSCC spheroids was related to expression of E-cadherin and the proliferation marker Ki67. In HNSCC cell lines the formation of tight regular spheroids was dependent on distinct E-cadherin expression levels in monolayer cultures, usually resulting in upregulation following aggregation into 3D structures. Cell lines expressing only low levels of E-cadherin in monolayers produced only loose cell clusters, frequently decreasing E-cadherin expression further upon aggregation. In these cell lines no epidermal growth factor receptor (EGFR) upregulation occurred and proliferation generally decreased in spheroids/aggregates independent of E-cadherin expression. In a second approach a global gene expression analysis of the larynx carcinoma cell line HLaC78 monolayer and the corresponding spheroids was performed. A global upregulation of gene expression in HLaC78 spheroids was related to genes involved in cell adhesion, cell junctions and cytochrome P450-mediated metabolism of xenobiotics. Downregulation was associated with genes controlling cell cycle, DNA-replication and DNA mismatch repair. Analyzing the expression of selected genes of each functional group in monolayer and spheroid cultures of all 12 cell lines revealed evidence for common gene expression shifts in genes controlling cell junctions, cell adhesion, cell cycle and DNA replication as well as genes involved in the cytochrome P450-mediated metabolism of xenobiotics.

Choquet H, Trapani E, Goitre L, et al.
Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1.
Free Radic Biol Med. 2016; 92:100-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.
METHODS: Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 'common Hispanic mutation' (CCM1-CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.
RESULTS: The CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.
CONCLUSIONS: Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.

Pellé L, Cipollini M, Tremmel R, et al.
Association between CYP2E1 polymorphisms and risk of differentiated thyroid carcinoma.
Arch Toxicol. 2016; 90(12):3099-3109 [PubMed] Related Publications
Differentiated thyroid carcinoma (DTC) results from complex interactions between genetic and environmental factors. Known etiological factors include exposure to ionizing radiations, previous thyroid diseases, and hormone factors. It has been speculated that dietary acrylamide (AA) formed in diverse foods following the Maillard's reaction could be a contributing factor for DTC in humans. Upon absorption, AA is biotransformed mainly by cytochrome P450 2E1 (CYP2E1) to glycidamide (GA). Considering that polymorphisms within CYP2E1 were found associated with endogenous levels of AA-Valine and GA-Valine hemoglobin adducts in humans, we raised the hypothesis that specific CYP2E1 genotypes could be associated with the risk of DTC. Analysis of four haplotype tagging SNPs (ht-SNPs) within the locus in a discovery case-control study (N = 350/350) indicated an association between rs2480258 and DTC risk. This ht-SNP resides within a linkage disequilibrium block spanning intron VIII and the 3'-untranslated region. Extended analysis in a large replication set (2429 controls and 767 cases) confirmed the association, with odds ratios for GA and AA genotypes of 1.24 (95 % confidence interval (CI) 1.03-1.48) and 1.56 (95 % CI, 1.06-2.30), respectively. Functionally, the minor allele was associated with low levels of CYP2E1 mRNA and protein expression as well as lower enzymatic activity in a series of 149 human liver samples. Our data support the hypothesis that inter-individual differences in CYP2E1 activity could modulate the risk of developing DTC suggesting that the exposure to specific xenobiotics, such as AA, could play a role in this process.

Xie YQ, Chen JM, Liu Y
Interaction of the CYP1A1 gene polymorphism and smoking in non-small cell lung cancer susceptibility.
Genet Mol Res. 2016; 14(4):19411-7 [PubMed] Related Publications
Many studies have shown that genetic factors, environmental factors, and bad living habits, especially smoking, are risk factors for lung cancer. However, not all smokers develop lung cancer, which may be related to different genetic backgrounds. Currently, most research has investigated the GSTM1, XRCC1, XRCC3, CYP2D6, and C188T genes. Little research has been done on the cytochrome P450 (CYP) 1A1 gene, and results have varied. In addition, no results have been reported on the interactive effects of smoking and the CYP1A1 gene on lung cancer development. We used polymerase chain reaction restriction fragment length polymorphism to detect the CYP1A1 genotype, and investigate the effects of the CYP1A1 gene deletion and smoking alone, and in combination, on non-small cell lung cancer susceptibility. We enrolled 150 non-small cell lung cancer patients and 150 healthy control subjects. Subjects' smoking habits and CYP1A1 gene polymorphism were analyzed to investigate their role in the occurrence of lung cancer. The CYP1A1 gene deletion was found in 73.3% of non-small cell lung cancer patients and 20.0% of healthy subjects. The OR value was 2.28 (P < 0.05). Among smoking subjects, 77.8% exhibited non-small cell lung cancer, significantly higher than the 27.3% in non-smokers (P < 0.05). The OR value for the interaction of smoking and CYP1A1 gene deletion was 5.60, larger than the product of their individual OR values. The CYP1A1 gene deletion is a lung cancer risk factor, and interacts with smoking in non-small cell lung cancer development.

Tian W, Liu J, Pei B, et al.
Identification of miRNAs and differentially expressed genes in early phase non-small cell lung cancer.
Oncol Rep. 2016; 35(4):2171-6 [PubMed] Related Publications
To explore the potential therapeutic targets of early‑stage non-small cell lung cancer (NSCLC), gene microarray analysis was conducted. The microarray data of NSCLC in stage IA, IB, IIA, and IIB (GSE50081), were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in IB vs. IA, IIA vs. IB, IIB vs. IIA were screened out via R. ToppGene Suite was used to get the enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the DEGs. The GeneCoDis3 database and Cytoscape software were used to construct the transcriptional regulatory network. In total, 25, 17 and 14 DEGs were identified in IB vs. IA, IIA vs. IB, IIB vs. IIA of NSCLC, respectively. Some GO terms and pathways (e.g., extracellular space, alveolar lamellar body, bioactivation via cytochrome P450 pathway) were found significantly enriched in DEGs. Genes S100P, ALOX15B, CCL11, NLRP2, SERPINA3, FoxO4 and hsa-miR-491 may play important roles in the development of early-stage NSCLC. Thus, by bioinformatics analysis the key genes and biological processes involving in the development of early-stage NSCLC could be established, providing more potential references for the therapeutic targets.

Veal GJ, Cole M, Chinnaswamy G, et al.
Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma.
Eur J Cancer. 2016; 55:56-64 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Variation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology.
METHODS: A total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients ≤ 18 years receiving cyclophosphamide (250 mg/m(2)), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed.
RESULTS: A two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 ± 1.07 versus 3.68 ± 1.43 L/h/m(2), respectively; mean ± standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 ± 0.11 L/h/m(2) versus 2.20 ± 0.31 L/h/m(2), P = 0.033) and dose 5 (3.12 ± 0.17 L/h/m(2) versus 4.35 ± 0.37 L/h/m(2), P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival.
CONCLUSION: The results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome.

Ohashi K, Hayashi T, Sakamoto M, et al.
Aldosterone-producing adrenocortical carcinoma with prominent hepatic metastasis diagnosed by liver biopsy: a case report.
BMC Endocr Disord. 2016; 16:3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aldosterone-producing adrenocortical carcinoma is a rare malignancy, which is usually diagnosed by histopathological examination of the excised tumor. In inoperable cases, aldosterone-producing ACC diagnosed by immunohistochemical staining of the metastatic tumor for Cytochrome P450 (CYP) 11β has not previously been reported and even in that case staining for adrenocortical-specific adrenal 4 binding protein/steroidogenic factor1 (Ad4BP/SF1) and steroidogenic enzymes has not been reported.
CASE PRESENTATION: We report the case of a 67-year-old Japanese woman with aldosterone-producing adrenocortical carcinoma. Laboratory findings showed severe hypopotassemia. Endocrinological examination revealed an increased plasma aldosterone concentration and suppressed plasma renin activity. Plasma dehydroepiandrosterone sulfate (DHEA-S) was elevated. Diurnal variation in serum cortisol was lost and administration of 1 mg and 8 mg dexamethasone did not suppress serum cortisol levels. From the 24-h urine collection sample, urine aldosterone and urine cortisol levels were greatly increased. Therefore, autonomous excess production was observed for the three adrenal cortex hormones. Abdominal computed tomography and magnetic resonance imaging showed a right adrenal tumor and a huge liver tumor. Adrenocortical carcinoma with metastatic liver cancer was strongly suggested, however surgery could not be considered due to stage IV disease: the liver tumor was too large and cardiac ultrasonography indicated that her cardiac function was poor. Therefore, a liver biopsy was taken to properly determine the diagnosis. Immunohistochemical stains for Ad4BP/SF1 and steroidogenic enzymes were positive. Ad4BP/SF-1 was originally identified as a steroidogenic, tissue-specific transcription factor implicated in the expression of the steroidogenic CYP gene encoding cytochrome P450s. Hence we could diagnose the patient as having adrenocortical carcinoma with metastatic liver cancer.
CONCLUSION: This rare case had severe hypopotassemia accompanied with not only increased cortisol and DHEA-S but also aldosterone. We reached the diagnosis of adrenocortical carcinoma with metastatic liver cancer based on positive immunohistochemical staining of Ad4BP/SF1 in the liver biopsy specimen. We have reported the first case of aldosterone-producing adrenocortical carcinoma diagnosed solely by immunohistochemical staining for adrenocortical-specific Ad4BP/SF1 and steroidogenic enzymes in a metastatic liver tumor.

Sankhwar M, Sankhwar SN, Abhishek A, et al.
CYP1B1 gene polymorphisms correlate with an increased risk of urinary bladder cancer in India.
Urol Oncol. 2016; 34(4):167.e1-8 [PubMed] Related Publications
PURPOSE: The urinary bladder is the target of several toxic compounds, which makes the bladder more prone to cancer. Cytochrome P450 1B1 enzyme is present in tumor tissues and metabolizes the polyaromatic carcinogens and activates several procarcinogens that cause DNA damage. We examined the functional single-nucleotide polymorphisms in the CYP1B1 gene to study their association with the urinary bladder cancer.
METHODS: We recruited 234 cases of pure urothelial and 258 bladder cancer-free control samples from the individuals visiting the clinic for various investigations. We genotyped 4 CYP1B1 single-nucleotide polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism analysis. The genotype data were analyzed by the Chi-square test. Haplotypes were constructed to evaluate the joint effect of the 4 polymorphisms.
RESULTS: Overall, 3 polymorphisms-rs10012, rs150799650, and rs1056827 (odds ratio [OR] = 2.34, CI: 1.59-3.45, P<0.0001; OR = 2.59, CI: 1.78-3.77, P<0.0001; OR = 2.32, CI: 1.57-3.44, P<0.0001, respectively) were found to correlate with urinary bladder cancer. Haplotype analysis suggested GTTC, GTTG, and ATGC to be the risk factors for bladder cancer.
CONCLUSIONS: Overall, 3 polymorphisms, rs10012, rs1056827, and rs150799650 in the CYP1B1 gene correlate with urinary bladder cancer significantly in the Indo-European population of Uttar Pradesh, India. Further investigations in other populations are advised.

Park YJ, Ahn HY, Kim HR, et al.
Ginkgo biloba extract EGb 761-mediated inhibition of aromatase for the treatment of hormone-dependent breast cancer.
Food Chem Toxicol. 2016; 87:157-65 [PubMed] Related Publications
Ginkgo biloba has been used in herbal medicines for thousands of years. Although a standard G. biloba extract, EGb 761 has been used to improve cognition in breast cancer patients, its effects on breast cancer are unknown. Therefore, we investigated the antitumorigenic effects of EGb 761 using an in vitro cell model and an in vivo xenograft model. EGb 761 significantly inhibited aromatase activity in aromatase over-expressing MCF-7 cells (MCF-7 AROM). In addition, EGb 761 exposure reduced cytochrome p450 aromatase (CYP19) mRNA and protein expression; CYP19 promoter I.3 and PII expression particularly decreased. These inhibitory effects on aromatase were accompanied by reduced 17β-estradiol levels in MCF-7 AROM cells. For elucidating antitumorigenic effects, MCF-7 AROM cells were implanted in BALB/c nude mice prior to oral EGb 761 treatment for 3 weeks. EGb 761 reduced the tumor size and significantly reduced tumor CYP19 mRNA expression. Taken together, our results indicated that EGb 761 inhibited aromatase and exerted antitumor effects on breast cancer cells both in vitro and in vivo. These findings suggest that EGb761 may be a useful aromatase inhibitor for the treatment for estrogen-sensitive breast cancer.

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