CYP1B1 Gene Details

Cytochrome P450 1B1 (CYP1B1) is a member of the cytochrome P450 (CYP450) gene family and one of the major enzymes involved in oestrogen hydroxylation, a key reaction in hormonal carcinogenesis. Therefore, CYP1B1 is commonly implicated in hormone-mediated tumours, such as prostate, breast, endometrial, and ovarian cancer. CYB1B1, the 4-hydroxylation catalyst, has been reportedly expressed at particularly high levels in these cancers and is responsible for hormone metabolism and the formation of toxic metabolites from both endogenous and exogenous molecules.

Studies investigating possible associations between CYP1B1 polymorphisms and cancer risk have been inconsistent. It is suggested that a possible role of ethnic differences in genetic backgrounds and the environment may modify the effect of polymorphisms on cancer susceptibility.

The human CYP1B1 gene, located at the 2p21–22 region, consists of three exons. The encoded CYP1B1 enzyme, a member of the larger CYP450 family, is involved in oestrogen and xenobiotic metabolism. Oestrogen hydroxylation and carcinogen activation, mediated by CYP450 enzymes, may occur in the liver, breast and prostate tissue, kidneys or other tissues.

CYP1B1 has been shown to catalyse 4-hydroxy oestrogen (4-OHE) formation in the breast, while it also bio-activates environmental pro-carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs). The enzyme also appears to play a role in the metabolism of certain anticancer agents used in the treatment of hormone-induced cancers. CYP1B1 is transcriptionally induced by compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin or dioxin and is regulated by several key transcriptional factors including the oestrogen receptor and aryl hydrocarbon receptor (AhR). 

Previous reports have suggested that oestrogens exert carcinogenic effects by stimulating cell proliferation, which results in an increase in DNA replication errors. However, more recent studies have revealed another important mechanism namely that the oxidative metabolism of oestrogens can form DNA-damaging species. This predominantly refers to the 3,4-quinone, which can react with DNA to cause the mutations and therefore leading to the initiation of cancer.

It is known that 4-hydroxy-oestrogens are subsequently oxidized to form oestradiol-3,4-quinone, accompanied by the generation of reactive oxygen species (ROS). Oestradiol-3,4-quinone reacts with DNA, mainly forming unstable N3-adenine and N7-guanine DNA adducts and generating apurinic sites thought to give rise to mutations and initiate breast cancer. Hydroxy-oestrogens and quinones are detoxified by conjugation reactions catalysed by phase II metabolizing enzymes such as catechol-O-methyltransferase (COMT) and glutathione S-transferases (GSTs).

The rs1056836 SNP (Val432Leu), a non-synonymous polymorphism occurring in the third exon of CYP1B1, entails a C-to-G mutation that results in the substitution of Leu for Val. The mutation occurs within the heme-binding domain of the enzyme, potentially influencing its function. Studies have demonstrated a remarkable 3-fold increase in enzymatic activity in Val-allele carriers.

Breast Cancer

Several family-based and case-controlled studies have demonstrated that individuals with the hyperactive GG genotype are at higher risk for breast cancer, although research seem contradicting.

A more recent prospective case-control study of 427 female cases and 536 case controls in a Chinese population found that women homozygous for the variant genotype (GG) exhibited a significantly reduced risk of breast cancer compared to those with the wild-type genotype (CC). 

Prostate Cancer

It is believed that the tissue-specific hydroxylation and carcinogen activation initiated by CYP1B1 may affect prostate cancer risk. Yang et al. (2012) performed a meta-analysis, including 2788 cases and 2968 controls, to determine prostate cancer risk and aggressiveness associated with the rs1056836 SNP. No significant association was found with overall prostate cancer risk, but the subgroup analyses revealed that the G-allele was significantly associated with an increased prostate cancer risk in Asians and in sporadic cancer subjects. No association was observed in Caucasians or mixed population subjects, neither was the rs1056836 SNP associated with prostate cancer aggressiveness.  

These results are supported by a subsequent meta-analysis (5999 cases and 5438 controls) from Zhang et al. (2013) in which, although there was no evidence that the Val432Leu polymorphism held significant association with prostate cancer in the overall population, the subgroup analysis by ethnicity revealed that the Val432Leu polymorphism was significantly associated with prostate cancer risk in Asians.

The G-allele was found significantly associated with prostate cancer risk in a population-based case-control study involving Caucasian men (1304 cases and 1266 controls). This association remained significant even after adjustment for multiple comparisons. A meta-analysis investigating the association between the Val432Leu polymorphism and urinary cancers (prostate, bladder and kidney cancer) from 17 studies (7944 cases and 7389 controls) revealed a significant association with overall urinary cancer risk. Furthermore, the authors identified reduced risk for CC genotypes in both prostate and overall urinary cancers, when studies were limited to Caucasian or Asian patients. 

Stop Smoking and/or Minimise Contact With Cigarette Smoke

The CYP1B1 metabolic enzymes can metabolize the pro-carcinogens in tobacco, such as aromatic ring hydrocar­bons, HAAs and PAHs, into car­cinogens, which in turn may activate oncogenes. A case-control study in a Chinese Han population from Yu et al. (2015) indicated that subjects who smoke or consume alcohol, especially heavy smokers and heavy drinkers, had a significantly increased risk of laryngeal cancer.

One study has found a significant increase in the breast cancer risk for smoking women in a Finnish population, especially for smokers homozygous for the Leu (C) allele.

Avoid Red Meat And High Cooking Temperatures

High temperature cooking methods such as pan-frying, grilling, oven-broiling or barbequing have been demonstrated to generate mutagens such as HCAs and PAHs. PAHs are deposited on the surface of smoked or grilled meat due to the pyrolysis of fat droppings, whereas HCAs are formed from the interaction of creatine/creatinine, amino acids and reducing sugars, which occurs at high temperatures. HCA formation increases as cooking temperature and duration increases.

These compounds are speculated to contribute to cancer risk; it may increase mutagenic frequency and has specifically been reported to induce damage to prostatic epithelium cells while PAH-DNA adducts have also been detected in human prostate cells. Native HCAs, PAHs and metabolites can reach the prostate gland via blood circulation where PAHs are activated by CYP1B1 to form PAH epoxides, which can be further activated to carcinogens or it can be detoxified by Phase II enzymes.

A multi-ethnic population-based case-study (1433 cases and 760 controls) by Catsburg et al. (2012) found a significant association between the Val-allele and an increased risk of localised prostate cancer.  PAHs that enter the prostate induce CYP1B1 expression; CYP1B1 has been found to be over-expressed in prostate carcinomas and can activate PAHs into mutagenic metabolites that form DNA adducts. The CYP1B1 protein coded by the Val-allele is reportedly more active than the one coded by the Leu-allele; therefore, supporting these authors’ finding of an association between the Valine (Val) allele and higher PCA risk.