CYP1A1 Gene Detail

Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) is a member of the larger CYP1 family: key enzymes in the metabolism of many endogenous substrates and exogenous carcinogens.

Research supports an association between the CYP1A1 Msp1 polymorphism (C-allele) and Ile462Val polymorphism (G-allele) and increased overall cancer risk. The mechanism behind increased cancer susceptibility has mainly been described as CYP1A1’s role in activating environmental pro-carcinogens and in catalysing the oxidative metabolites of oestrogen i.e. catechols and oestrogen quinones. Since certain compounds are more likely to influence cancer risk by the formation of harmful DNA adducts in the presence of a CYP1A1 polymorphism, it is recommended to avoid contact with environmental pro-carcinogens such as polycyclic aromatic hydrocarbons (PAH), aromatic amines, nitrates and smoking of any kind as a preventative strategy.

Some findings regarding these polymorphisms and cancer risk remains contradictory, which indicates that polymorphisms of CYP1A1 might exert different effects in different types of cancers. The effects of genetic polymorphisms on can­cer risk also seem to be affected by ethnic back­ground.

Cytochromes P450 are heme-containing enzymes critical to phase I-dependent metabolism (such as C-, N- and S-oxidation and dealkylation) of drugs and other xenobiotics. The larger family of CYP enzymes has been implicated in cellular functions such as the metabolism of eicosanoids, the biosynthesis of cholesterol and bile acids, synthesis and metabolism of steroids and vitamin D3, synthesis and degradation of biogenic amines, and the hydroxylation of retinoic acid and presumably other morphogens. Many polymorphisms have been described in the CYP genes and these are thought to play an important role in determining individual cancer susceptibility.

The CYP1A1 gene is present on chromosome 15q24.1 and consists of 7 exons. It encodes for the enzyme aryl hydrocarbon hydroxylase (AHH) which is mainly expressed extra-hepatically, especially in epithelial tissues. This enzyme is considered important for the metabolism of many endogenous substrates and exogenous carcinogens such as polycyclic aromatic hydrocarbons (PAH), heterocyclic amines, dibenzofurans, biphenyls, aflatoxin B1 and oestrogen.

The expression of CYP1A1 is regulated by a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR), which is part of phase I reactions in drug metabolism. Under normal physiologic conditions, CYP1A1 expression is induced by PAHs via activation of the AhR. The AhR complex then translocates to the nucleus and binds to its partner protein, aryl hydrocarbon receptor nuclear translocator (ARNT). The AhR/ARNT heterodimer binds to specific DNA recognition sites termed xenobiotic responsive elements (XREs) located upstream of the transcription start site and initiates CYP1A1 transcription. Previous studies have shown that the expression level of CYP1A1 is frequently upregulated in several human tissues due to hypomethylation of XRE sites.

CYP1A1 drives the first step in the metabolism of PAHs, reactive electrophilic metabolites that are formed during the incomplete combustion of coal, oil, gas and other organic substances like tobacco, thus it may contribute to the formation of highly reactive intermediates when these compounds bind to DNA to create PAH-DNA adducts. Should these adducts be left unrepaired, it can instigate or accelerate carcinogenesis Tobacco smoking has also been described as one supposed mechanism affecting XRE methylation status of CYP1A1.

Literature explains that the CYP1A1 polymorphisms may be risk factors for several malignancies as alterations in structure and function may influence its role in the detoxification of environmental carcinogens and metabolic activation of dietary compounds that would normally protect against cancer. Polymorphisms of the CYP1A1 enzymes may contribute to the variable susceptibility to carcinogenesis by altering the level of gene expression or messenger RNA stability, resulting in highly inducible activity of the enzyme.

Msp1 T>C

The Msp1 T>C polymorphism (rs4646903, T6235C / T3801C, 2A or m1) is described as a functional, non-synonymous polymorphism occurring in the non-coding 3’-flanking region of the CYP1A1 gene. The T-to-C mutation results in the creation of a new Msp1 restriction site.

A large meta-analysis of 139 publications with 148 case-controlled studies for Msp1 found that the CC genotype was associated with increased risk of cancers, especially lung and cervical cancer among Asians and mixed population (composed of different ethnic groups). To support these findings, a meta-analysis within a Chinese-only population (22 studies comprising 3016 cases and 3932 controls) found strong evidence of a significant association between the Msp1 polymorphism and lung cancer risk. 

A>G Ile462Val

The A-to-G transition in exon 7 of the CYP1A1 gene results in the replacement of Isoleucine (Ile) with Valine (Val) at codon 462, which is described as a heme-binding site. This functional, non-synonymous polymorphism (rs1048943, A4889G / A2455G, 2C or m2) is said to potentially influence the balance between metabolic activation and detoxification of toxins by enhancing catalytic activity – this may ultimately lead to individual susceptibilities to cancer. It has also been reported that this variant significantly increases the catalytic activity for all hydroxylation sites toward substrates such as 17β-estradiol (E2) and estrone (E1), most significantly for 2-hydroxylation. 

The meta-analysis from Wu et al. (2012) considered 126 publications with 134 case-controlled studies to conclude that the GG genotype was associated with an increased risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer among Caucasians and Asians, but not in Africans or in populations of mixed descent. These findings are conflicting with previous data as other researchers reported that the Ile462Val GG polymorphism is not associated with an increased risk of esophageal carcinoma and prostate cancer. Wu et al. (2012) noted that consequently large-scale, detailed and mechanistic studies are needed to confirm these relationships.  

In support of Wu et al. (2012), but in contrast to an earlier meta-analysis from Shaik et al. (2009), an updated meta-analysis from Li et al. (2012) reported that the Ile462Val polymorphism of CYP1A1 results in a significantly increased susceptibility to prostate cancer in all genetic models. This finding is supported in the most recent 2019 meta-analysis from Zhu et al. (2019), which concluded that the Ile462Val polymorphism is significantly associated with prostate cancer susceptibility in the overall population, as well as the Asian populations, but not in Caucasian men.

Cervical cancer is described as a complex disease and is essentially considered an outcome of viral-induced carcinogenesis. The CYP1A1 enzyme is involved in the oxidation of oestrogen to catechols and oestrogen quinones that forms mutagenic stable and depurinating DNA adducts, facilitating Human Papilloma Virus (HPV) integration in the host genome. Cervical carcinogenesis is said to occur due to the synergistic effect of HPV infection and oestrogen metabolism.  

A significant increase in cervical cancer risk was found amongst Caucasian G-allele (Val) carriers, consistent with previous findings from Sergentanis et al. (2012) The subgroup analysis based on ethnicity indicated that the CYP1A1 Ile462Val polymorphism played different roles in Asian and Caucasian populations. In the Caucasian population, people with Ile462Val G or Val-allele might have a higher risk of cervical cancer, whereas in Asians, no significant correlation had been found. They did mention, however, that only 2 studies were included for the Asian population, thus the interpretation of results should be done cautiously and further studies were needed to validate the results. A meta-analysis published in the same year, performed among Indian women, was not included in the Ding et al. (2018) analysis. Their findings, after analysing 29 genetic association studies regarding cervical cancer in India, revealed significant association of rs1048943 with cervical cancer.

Breast cancer risk associated with the Ile462Val polymorphism has been investigated due to the involvement of CYP1A1 in oestrogen metabolism. A meta-analysis from Sergentanis et al. (2009), which examined the Ile462Val polymorphism and breast cancer risk, included separate analyses on Caucasian, Chinese, and African populations, as well as on premenopausal and postmenopausal women. A total of 29 studies comprising 12 257 cases and 20 379 controls were considered. The meta-analysis reported a significantly increased breast cancer risk only in Caucasian subjects homozygous for the Val-allele (GG genotype). No association with breast cancer risk in Chinese subjects, or specifically in premenopausal/postmenopausal women were found. This is in contrast with previous meta-analyses, which either reported no association with breast cancer risk (Masson et al. in 2005) or reported an association only in East-Asians and in pre-menopausal women (Chen et al. in 2007). The authors explained these disparities: fewer studies were previously included, also studies were grouped differently to compose East Asian versus Caucasian populations. However, given the larger sample of studies in the present meta-analysis, adapting the population groupings to match the previous meta-analysis still did not lead to any different results.

Stop Smoking and/or Minimise Contact With Cigarette Smoke

Tobacco smoke contains many carcinogens and procarcinogens, such as benzopyrene and nitrosamine. These compounds are metabolized by the phase I enzymes, including CYP family enzymes, and converted to inactive metabolites by the phase II enzymes. Also present in tobacco smoke, PAH exposure may lead to PAH-DNA adduct formation and increased oncogenesis.

Smoking has been recognized as risk factor for lung cancer, breast cancer, renal cell carcinoma, oral cancer, cervical cancer, and colorectal cancer.

Msp1 T>C

The Msp1 C-allele has showed a significant association with smoking for prostate cancer risk in various studies, although some results have been conflicting. A study from Mitsui et al. (2016) demonstrated that CYP1A1 is an important oncogene in prostate cancer as it is upregulated by DNA promoter hypomethylation. Tobacco smoking can cause a further reduction of methylation at the CYP1A1 distal enhancer that may lead to carcinogen activation through increased CYP1A1 expression. Altogether their findings demonstrate that tobacco smoking may contribute to the pathogenesis of prostate cancer and that inhibition of CYP1A1 may have therapeutic potential.

Smokers carrying the Msp1 C-allele has also been demonstrated to have an increased risk for renal cell carcinoma.

A>G Ile462Val

Many of the thousands of chemical compounds contained in tobacco smoke are considered mammary carcinogens. The activity of CYP1A1 may influence breast carcinogenesis via at least two distinct pathways, tobacco metabolites and oestrogen metabolism. A case-control study amongst 297 Spanish women supported the hypothesis that CYP1A1 Ile462Val, in association with long periods of active smoking, could be a breast cancer risk factor. When smokers were stratified by smoking duration however, researchers observed that only long-term smokers (≥ 20 years) with the Ile462Ile genotype (AA) was associated with increased risk of breast cancer. The authors speculated that their results support the main effect of CYP1A1 in estrogenic metabolism rather than in tobacco carcinogen activation in breast cancer. Smoking induces CYP1A1 and the effect of its polymorphisms in estrogenic metabolism is upregulated in a dose-dependent manner.