Cytochrome P450 CYP2D6.

Altered expression of CYP2D6 (debrisoquine hydroxylase), resulting from genetic polymorphism at the CYP2D6 gene locus, is responsible for pronounced interindividual variation in the metabolism of many clinically important drugs. Although CYP2D6 substrates are structurally diverse, most are small molecules that interact with the protein via an electrostatic interaction between a basic nitrogen which is common to the majority of CYP2D6 substrates and an aspartic acid residue in the active site of the protein. As CYP2D6 substrates have a wide range of pharmacological functions, any variation in CYP2D6 expression can have profound clinical consequences. CYP2D6 activity can be determined both by phenotyping methods with a variety of probe drugs and by genotyping methods where PCR-based techniques are used to investigate the inheritance of individual CYP2D6 alleles. Allele frequencies have been shown to vary widely between populations of different racial origin. For example, the PM genotype is particularly rare in Orientals. The inheritance of certain CYP2D6 allelic variants has been associated with altered susceptibility to Parkinson's disease and several types of cancer.     

Cytochrome P450 1A1 (CYP1A1) polymorphism and susceptibility to esophageal cancer: an updated meta-analysis of 27 studies

Cytochrome P450 1A1 (CYP1A1) polymorphisms are known to play a crucial role in the development and metastasis of malignant diseases including esophageal cancer. However, the results of previous studies investigating the association between CYP1A1 polymorphisms and esophageal cancer risk have been inconsistent. This meta-analysis of 27 eligible studies, encompassing 4,215 esophageal cancer cases and 6,339 control subjects, pooled the odds ratios (ORs) with corresponding 95 % confidence intervals (95 % CI) to assess this association. The effects of ethnicity (Caucasian and Asian) and histopathology type (esophageal squamous cell carcinoma and esophageal adenocarcinoma) were considered in subgroup analyses. A significant association was observed between the CYP1A1 Ile/Val gene polymorphism and esophageal cancer in all of the genetic models (Ile/Val vs. Ile/Ile, OR?=?1.41, 95 % CI?=?1.25–1.58; Val/Val vs. Ile/Ile, OR?=?1.94, 95 % CI?=?1.34–2.82; Ile/Val?+?Val/Val vs. Ile/Ile, OR?=?1.49, 95 % CI?=?1.33–1.66). The subgroup analysis based on ethnicity showed that the association between the CYP1A1 Ile/Val polymorphism and esophageal cancer existed in Asian and Caucasian populations. However, no association was observed between the CYP1A1 MspI polymorphism and esophageal cancer in either subgroup or in the overall population. These results suggested that the CYP1A1 Ile/Val polymorphism was associated with an increased risk of esophageal cancer, whereas the CYP1A1 MspI polymorphism may not have increased susceptibility to esophageal cancer. Further studies are required to confirm these findings.     

Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer.

Ovarian cancer is the most frequent cause of death from gynaecological malignancies world wide. Little improvement has been made in the long-term outcome of this disease, with the 5-year survival of patients only 30%. This poor prognosis is due to the late presentation of the disease and to the unpredictable response of ovarian cancer to chemotherapy. The cytochrome P450 enzymes are a superfamily of haemoproteins, known to be involved in the metabolic activation and/or detoxification of a number of anti-cancer drugs. CYP1B1 is a tumour-related form of cytochrome P450 which is over expressed in a wide variety of primary tumours of different histological type. The presence of CYP1B1 may be of importance in the modulation of these tumours to anti-cancer drugs. We have conducted a comprehensive immunohistochemical investigation, into the presence of cytochrome P450 CYP1B1 in primary and metastatic ovarian cancer. The key findings of this study are the increased expression of CYP1B1 in the majority of ovarian cancers investigated (92%), with a strong correlation demonstrated between CYP1B1 expression in both primary and metastatic ovarian cancer (P = 0.005 Spearman's rank correlation test). In contrast no detectable CYP1B1 was found in normal ovary.     

Steroid metabolism gene CYP17 polymorphism and the development of breast cancer.

The potential role of the polymorphism in the CYP17 gene was evaluated in a case-control study with 483 incident breast cancer patients and 482 population controls, all of homogenous Finnish origin. Our data disagree with the earlier suggestions that the minor A2 variant of CYP17 would pose an increased risk for developing advanced breast cancer. In contrast, a tendency of inverse association was found for premenopausal women carrying the A2 allele containing genotypes with a multivariate adjusted odds ratio of 0.58 approaching statistical significance (95% CI, 0.31-1.07). Agreeing with previous observations, the protective effect of later age at menarche (> or =13 years) was mainly limited to women with A1/A1 genotype, although this could only be seen in premenopausal women (odds ratio, 0.34; 95% CI, 0.15-0.76). Similarly, we found a remarkably lower risk for premenopausal women with at least one child (odds ratio, 0.22; 95% CI, 0.07-0.62) to be mainly attributable to the A1/A1 genotype. CYP17 genotypes may thus modify individual breast cancer proneness in certain subpopulations, although they appear not to have any major modifying role in the risk of this malignancy overall. Because these findings are based on relatively small numbers in stratified analysis, they should, however, be interpreted with caution before being confirmed in future studies.     

Modulation of cyclophosphamide-based cytochrome P450 gene therapy using liver P450 inhibitors

The sensitivity of tumors to cyclophosphamide (CPA) and other anticancer prodrugs can be substantially enhanced by transduction of tumors with a prodrug-activating mammalian cytochrome P450 (CYP) enzyme in combination with the flavoenzyme P450 reductase. This gene therapy strategy provides for intratumoral prodrug activation, but is also associated with a high level of hepatic prodrug activation, which reduces the extent of intratumoral prodrug activation and contributes to systemic drug toxicity. To address this issue, five P450 inhibitors were tested for their ability to block liver CYP2C-catalyzed CPA activation selectively, i.e., without inhibiting the corresponding intratumoral activation of CPA catalyzed by a transduced CYP2B enzyme. In vitro studies revealed that the P450 inhibitors 1-aminobenzotriazole and DDEP were preferentially inhibitory toward CYP2C-dependent liver microsomal CPA activation, whereas the P450 inhibitor SKF-525A inhibited CYP2C- and CYP2B-dependent CPA activation without P450 form selectivity. By contrast, the P450 inhibitors chloramphenicol and metyrapone preferentially inhibited CYP2B-dependent CPA activation. Rat pharmacokinetic studies confirmed the inhibitory action of these compounds in vivo, with up to a 4-fold decrease in C(max) and a 7-fold increase in apparent half-life of the activated CPA metabolite, 4-hydroxy-CPA, seen in the case of 1-aminobenzotriazole. Although the rate of hepatic CPA activation could thus be decreased substantially by P450 inhibitor treatment, the net extent of hepatic CPA activation was only modestly decreased, as judged by plasma area-under-the-curve values for 4-hydroxy-CPA. Moreover, P450 inhibitor treatment did not decrease CPA's host toxicity and did not enhance the tumor growth delay response to CPA in rats bearing CYP2B1-transduced gliosarcomas. These findings are discussed in the context of P450-based gene therapy strategies and ongoing efforts to enhance anticancer drug activity by increasing the exposure of P450-expressing tumors to the P450-activated prodrug CPA.     

Cytochrome P450 1B1 gene polymorphisms and postmenopausal endometrial cancer risk.

Estrogen unopposed by progestins is a key factor in endometrial cancer etiology. Cytochrome P450 1B1 (CYP1B1), responsible for the 4-hydroxylation of estrogen, may be important in endometrial carcinogenesis, either as a regulator of estrogen availability or as a producer of potentially genotoxic estrogen metabolites. We investigated the association of CYP1B1 genotype and endometrial cancer risk in a population-based case-control study of postmenopausal Swedish women. We used the Expectation-Maximization algorithm to estimate the haplotype frequencies in the population and calculated odds ratios and 95% confidence intervals from conditional logistic regression models. In stratified analysis, we investigated the possible effects of CYP1B1 genotype on endometrial cancer risk in subgroups defined primarily by menopausal hormone use and also by body mass index, smoking, use of combined oral contraceptives, and family history. We genotyped 689 cases and 1,549 controls for the CYP1B1 single nucleotide polymorphisms m2, m3, and m4 and estimated the haplotype frequencies among controls to 0.086, 0.291, 0.452, and 0.169 for the CYP1B1*1, CYP1B1*2, CYP1B1*3, and CYP1B1*4 alleles, respectively. We found no evidence for an overall association between CYP1B1 genotype and endometrial cancer risk, nor was there any clear indication of gene-environment interaction.     

Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma.

PURPOSE: Osteosarcoma, the most common pediatric primary bone tumor, is an aggressive malignancy with a tendency for early pulmonary metastasis. A reliable biomarker to predict clinical outcome at diagnosis has not yet been identified. To date, pathological review of neoadjuvant chemotherapy-induced necrosis is the most useful determinant of which patients are likely to develop metastatic disease. There is a clinical need to identify patients who will benefit from more aggressive preoperative therapy or perhaps require less aggressive chemotherapy. More than 30 human P450 isoenzymes have been characterized, with at least nine possessing some clinical relevance. One of these, CYP3A4/5 is involved in metabolic activation and detoxification of a wide number of carcinogens and chemotherapeutic agents, including many drugs that are useful in the treatment of osteosarcomas. MATERIALS AND METHODS: Osteosarcoma tissue microarray blocks containing biopsies from 18 primary tumors were used to analyze the expression of P450s 1A1/2, 1B1, 2B6, 2D6, and 3A4/5 by enzyme-linked avidin-biotin complexed immunohistochemistry. The frequencies of expression were 83%, 67%, and 83% for P450s 1A1/2, 1B1, and 3A4/5, respectively. P450s 2B6 and 2D6 were not detectable. RESULTS: These results were extended by developing a fluorescent-based quantitative immunocytochemistry technique to assess the levels of CYP3A4/5 in 18 paraffin-embedded primary biopsy sections. Expression of CYP3A4/5 was found to be significantly higher in primary biopsies of patients who developed distant metastatic disease compared with biopsies from patients with nonmetastatic disease (P = 0.0004). CONCLUSION: High cytochrome P450 CYP3A4/5 expression may predict metastasis and poor prognosis in osteosarcomas. Its use as a biomarker of therapeutic response will have implications for the treatment of these tumors.     

细胞色素P450 3A4基因多态性及与肝癌易感性研究

目的 探讨细胞色素P450 3A4(CYP3A4)基因的多态性与肝癌的关系。方法 应用聚合酶链反应（PCR）、变性梯度凝胶电泳（DGGE）、单链构象多态（SSCP）和DNA测序技术，对84例肝癌患者和144例健康对照的CYP3A4基因的多态性进行了研究。结果 通过对CYP3A4基因10个外显子的检测，发现2例肝癌患者的第7外显子第15742位核苷酸发生了A→G转换，使得第183位氨基酸残基由天冬酰胺转变为丝氨酸；发现第10内含子存在一单核苷酸多态，表现第20338位核苷酸发生了G→A转换。病例组G／G、G／A和A／A基因型频率分别为59.52％,36.90%和3.58%；对照组则为59.72%，33.33%和6.95％。两组比较没有统计学差异。结论 CYP3A4基因可能高度保守，虽有突变，但属罕见。     

Polymorphisms in the human aromatase cytochrome P450 gene (CYP19) and breast cancer risk

The aromatase enzyme catalyses the conversion of androgens to oestrogens in the oestrogen biosynthesis pathway. Because increased exposure to oestrogens is considered to be a risk factor for breast cancer, the human aromatase gene (CYP19) is a plausible candidate for low penetrance breast cancer susceptibility. Preliminary reports have suggested that specific alleles of a TTTA repeat may be associated with differences in breast cancer risk. We have identified two new polymorphisms in the CYP19 gene: a TCT insertion/deletion in intron 4 and a G-->T substitution in intron 6, which have rare allele frequencies of 0.35 and 0.45, respectively, in the British population. Comparison was made between the frequencies of these alleles and those of the TTTA repeat in up to 599 breast cancer cases and 433 normal controls from the East Anglian, British population. We found strong linkage disequilibrium between the alleles of these three loci, but no significant association of any alleles with breast cancer risk. The maximum odds ratios observed were: 1.03 (95% CI 0.68-1.55) for the intron 4 TCT insertion/deletion polymorphism [del/del versus ins/ins]; 1.56 (95% CI 0.63-3.83) for the intron 4 [TTTA](10) allele; 1.29 (95% CI 0. 75-2.21) for the intron 6 G-->T polymorphism [TT versus GG]. We conclude that the CYP19 gene has no major role in common breast cancer incidence in the British population.     

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR = 3.14, 95% confidence interval (95% CI) = 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4.9-fold more likely to have the CYP2A6 homozygote deletion genotype (OR = 4.91, 95% CI 1.17-20.52). Stratifying by smoking status, we did not find the risk of CYP2A6 gene deletion allele in gastric adenocarcinoma. The CYP2E1 polymorphism detected by RsaI was not significantly different between gastric adenocarcinoma patients (40.8%) and the control population (44.3%). No statistically significant changes were observed when the CYP2E1 genotype was examined relative to tumor differentiation and smoking status. These results suggest that the CTY2A6 deletion is associated with gastric adenocarcinoma among Japanese populations.     

A polymorphism in the CYP17 gene is associated with male breast cancer.

The CYP17 gene codes for the cytochrome P450c17alpha enzyme that is involved in the synthesis of oestrogens. This case-control study from the South East of Scotland shows that a polymorphism of the CYP17 gene is associated with an increased risk of male breast cancer.     

The relationship between a polymorphism in CYP17 with plasma hormone levels and prostate cancer.

The A2 allele of the CYP17 gene has been thought to be associated with increased functional activity of this steroidogenic enzyme. Consequently, the A2 allele has been examined as a biomarker of individual susceptibility to hormone-related diseases among men and women. We prospectively assessed the association between the A2 allele of CYP17 and prostate cancer risk among 590 cases and 782 controls in a case-control study nested within the Physicians' Health Study cohort. We also evaluated associations between CYP17 genotype and plasma steroid hormones among controls and the potential interaction between CYP17 and SRD5A2 V89L polymorphisms in relationship with prostate cancer risk and circulating steroid hormone levels. We observed a borderline significant association between the A2 allele and prostate cancer risk (odds ratio, 1.23; 95% confidence interval, 0.99-1.54), however, we did not observe evidence of a gene-dosage effect (versus A1/A1 genotype: A1/A2 genotype; odds ratio, 1.26; 95% confidence interval, 0.99-1.59; A2/A2 genotype: odds ratio, 1.17; 95% confidence interval, 0.85-1.61). The A2 allele was not overrepresented among cases with advanced prostate cancer. Among controls, carriers of the A2 allele had steroid hormone levels similar to noncarriers. We also found no evidence of a gene-gene interaction between CYP17 and SRD5A2 V89L polymorphisms on prostate cancer risk or endogenous steroid hormone levels. These results suggest that CYP17 genotype may possibly confer a small increased susceptibility to prostate cancer but is not a strong predictor of endogenous steroid hormone levels in men.     

The T/C polymorphism of the CYP17 gene and G/A polymorphism of the CYP19 gene in endometrial cancer

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. The CYP17 and CYP19 genes encode 17 hydroxylase/17,20-lyase and aromatase, respectively, both involved in sex hormone synthesis. The gene CYP17 and CYP19 are polymorphic and gene variability could contribute to the level of protein biosynthesis. In the present work the distribution of genotypes and frequency of alleles of the C/T polymorphism in promoter region of CYP17 and G/A polymorphism at position Val80 in CYP19 in subjects with endometrial cancer were investigated. Paraffin embedded tumour tissues were obtained from 100 women with endometrial cancer. DNA from normal endometrial tissue (n = 106) served as control. The polymorphisms were determined by PCR-RFLP. The distribution of the genotypes of the C/T polymorphism of CYP17 and G/A polymorphism of CYP19 in both control and patients did not differ significantly (p > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no significant differences (p > 0.05) in genotype distributions and allele frequencies between subgroups assigned to histological stage.The results suggest that C/T polymorphism of the CYP17 gene as well as G/A polymorphism of CYP19 may not be linked with onset and development of endometrial cancer.     

Association between CYP17 gene polymorphism and risk of breast cancer in young women.

Long-term exposure to oestrogens is a well-recognised risk factor for breast cancer, whereas little is known about the influence of polymorphisms of genes involved in oestrogen biosynthesis and metabolism. A candidate, containing a single bp polymorphism, T-->C, (designated, A2 allele), might be the CYP17 gene, which codes for an enzyme involved in oestrogen synthesis. This polymorphism creates an additional Sp1-type promoter site (CCACC box), which has been shown to be associated with increased serum oestrogen levels. We performed a case-control study, to evaluate association of the CYP17 gene polymorphism with risk of breast cancer in young women (younger than 37 years). We found a statistically significant increased risk in carriers of at least 1 A2 allele [odds ratio (OR), 2.0; 95% confidence interval (CI), 1.1-3.5, p = 0.027], and a trend toward a gene-dose effect illustrated by a slightly higher risk for A2-homozygous subjects (OR, 2.8) than for heterozygous women (OR, 1. 9). Furthermore, when we investigated the CYP17 genotype in relation to tumour characteristics, breast cancer patients with 1 or 2 A2 alleles tended to have lower oestrogen receptor levels (risk ratio, 0.70; CI, 0.41-1.2, p = 0.44). Our findings suggest that CYP17 gene polymorphism influences breast carcinogenesis in young women. Int. J. Cancer (Pred. Oncol.) 84:350-353, 1999.     

Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study

Introduction  

Breast cancer risk may be determined by various genetic, metabolic, and lifestyle factors that alter sex hormone metabolism. Cytochrome P450 1A2 (CYP1A2) is responsible for the metabolism of estrogens and many exogenous compounds, including caffeine.     

Risk of endometrial cancer and estrogen replacement therapy history by CYP17 genotype

Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometrial cancer. We examined the association between endometrial cancer risk and estrogen replacement therapy (ERT) by CYP17 genotype using 51 incident cases and 391 randomly selected controls from a multiethnic cohort in Hawaii and Los Angeles, California. The relative risk of endometrial cancer was calculated for ever use versus never use of ERT by CYP17 genotype (TT, TC, and CC). We found that women who reported ever taking ERT were more than twice as likely to develop endometrial cancer as women who never took ERT [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.19-4.23]. Among these women, the risk of endometrial cancer was higher for women homozygous for the CYP17 T allele (OR, 4.10; 95% CI, 1.64-10.3), but not for women with the C allele (OR, 1.31; 95% CI, 0.53-3.21). These preliminary findings suggest that CYP17 or other variants in estrogen biosynthesis or metabolism pathways may be potential markers of endometrial cancer susceptibility due to ERT.