The Relationship between Aryl Hydrocarbon Hydroxylase and Polymorphisms of the CYP1A1 Gene

Abstract

We examined the relationship between aryl hydrocarbon hydroxylase (AHH) and the frequency of a Msp I mutation in the 3′‐flanking region of cytochrome P450 (CYP) 1A1 (Mspl polymorphism) and another mutation in exon 7 (Ile‐Val polymorphism) in 84 healthy male subjects in Fukuoka, Japan. AHH inducibility (3‐methylcholanthrene (MC)‐induced AHH activity/non‐induced AHH activity) was correlated with the MspI polymorphism (P<0.0001) and age class (P=0.015), whereas no correlation was found for the Ile‐Val polymorphism (P=0.509). Age‐adjusted AHH inducibility (mean±SE) of the predominant homozygote (genotype A), the heterozygote (genotype B) and a homozygote rare allele (genotype C) genotypes was 4.89±0.36, 4.82±0.29 and 13.61±1.44, respectively. The genotype C showed much higher AHH inducibility than genotypes A and B (P<0.001), while no significant difference was observed between genotypes A and B. Non‐induced AHH activity was also correlated with these polymorphisms. The AHH activity of a homozygous mutant Val/Val genotype (0.076±0.010 pmol/min/106 cells) was significantly higher (P<0.05) than that of the wild‐type homozygous Ile/Ile (0.044±0.004 pmol/min/106 cells) and heterozygous Ile/Val (0.047±0.007 pmol/min/106 cells) genotypes. Our study suggests that the genotypes C and Val/Val, which are more frequent in smoking‐related lung cancer, are closely related with high AHH inducibility and high non‐induced AHH activity, respectively. Thus, the positive relationship between AHH inducibility and lung cancer is supported by our study. If our results are confirmed and the assessment of genotype becomes feasible on a population basis, identification of smokers who have genetically high susceptibility to lung cancer (genotype C or Val/Val) may become important for the prevention of lung cancer.

Cytochrome P450 1A1 (CYP1A1) T3801C and A2455G polymorphisms in breast cancer risk: a meta-analysis

“…The T3801C and A2455G alleles were reported to encode an inducible form of CYP1A1 Kiyohara et al 1996). Although CYP1 enzymes are responsible for metabolically activating PAHs and aromatic amines, Nebert et al (2004) proposed that whether CYP1A1 detoxifies or causes toxicity depends on many factors, such as sub-cellular content and location, amount of Phase II metabolism, degree of coupling to Phase II enzymes, and cell type-and tissue-specific context, as well as pharmacokinetics.…”

“…Crofts et al (1993) reported a threefold elevation in CYP1A1 enzymatic activity associated with A2455G G/ G genotypes. The T3801C allele was also reported to encode an inducible form of CYP1A1 (Kiyohara et al 1996).…”

Genetic polymorphisms of cytochrome P4501A1 and oesophageal squamous-cell carcinoma in Taiwan

“…These two findings suggest that the inducible CYP1A1 gene might contribute to oesophageal cancer development. In two in vitro studies, Kiyohara et al (1996) examined the relationship between AHH inducibility (3-methylcholanthrene (MC)-induced AHH activity/non-induced AHH activity) and the frequency of CYP1A1 MspI and exon 7 polymorphisms in peripheral lymphocytes in 84 healthy Japanese male subjects in vitro. They found the ageadjusted AHH inducibility (mean+standard error) of the wildtype, heterozygous, and homozygous variants of the CYP1A1 MspI gene to be 4.89+0.36, 4.82+0.29, and 13.61+1.44, respectively.…”

Ovarian Cancer Risk and Polymorphisms Involved in Estrogen Catabolism

“…Genotypic variation resulting in a phenotype that increases 2-OH may decrease risk of carcinogenesis by two possible mechanisms: competitively reducing potentially genotoxic 4-OH intermediates and increasing 2-OH intermediates, which can be methylated to 2-MeO-E2, an antiangiogenic metabolite (26). Functional studies have shown increased enzyme activity with m1 ''C,'' m2 Val 462 , and m3 ''C'' alleles and reduced activity with m4 Asn 461 allele (27)(28)(29)(30). Similar to results of previous studies, we observed no association between the CYP1A1 m1, m2, and m4 polymorphisms and epithelial ovarian cancer (9)(10)(11).…”