Genetic Polymorphism of CYP2A6 and Tobacco-Related Cancer Risk: From the Establishment of Genetically Engineered Salmonella to Large Scale Epidemiology

Abstract

Most mutagens/carcinogens are metabolically activated by enzymes such as cytochrome P450 to exert their mutagenicity or carcinogenicity. Since the catalytic properties of cytochrome P450 vary among animal species, it was necessary to establish a mutation-detection system carrying human cytochrome P450 to estimate if the chemicals are mutagenic in humans. For this purpose, we introduced genes for human cytochrome P450 together with NADPH-cytochrome P450 reductase to establish humanized Salmonella typhimurium. Using the genetically engineered Salmonella typhimurium, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype towards (＋)-cis-3,5-dimethyl-2-(3-pyridyl)thiazoline-4-one hydrochloride (SM-12502), we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Taking these results into account, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk to tobacco-related lung cancer. In accordance with our hypothesis, our large scale epidemiological studies clearly indicated that smokers homozygous for the CYP2A6*4C allele showed much smaller odds ratios towards cancer risk. Other mutant alleles reducing the CYP2A6 activity besides the CYP2A6*4C allele also reduced the risk for lung cancer in smokers, particularly squamous cell carcinoma and small cell carcinoma frequently seen in smokers. 8-Methoxypsoralen, an inhibitor of CYP2A6, e‹ciently prevented the occurrence of adenoma caused by NNK in A/J mice.

Polymorphism in cytochrome P4502A6 reduces the risk to head and neck cancer and modifies the treatment outcome

“…Cases with mutant alleles of CYP2A6 also eliminated significantly higher concentrations of tobacco‐specific carcinogens in urine isolated from HNSCC or lung cancer patients, though this was also attributed to other CYPs (Tiwawech et al, 2006). In vitro studies have also shown that deletion allele of CYP2A6 ( CYP2A6*4C ) exhibited no enzymatic activity, and its variants show markedly reduced activity toward tobacco‐specific carcinogens such as nicotine and nitrosamines (Hosono et al, 2017; Kamataki, 2006). Likewise, polymorphism in the regulatory region ( CYP2A6*9 ) results in about a 50% decrease in the transcription rate which leads to reduced enzyme activity resulting in lowered nicotine clearance (Benowitz et al, 2006).…”

“…CYP2A6 , which catalyzes the metabolism of pharmaceutical compounds including coumarin, nicotine, and chemotherapeutic drugs such as tegafur (TF) (McDonagh et al, 2012), along with CYP2B6 is also involved in the metabolism of tobacco‐specific nitrosamines such as 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol (NNAL), important in causing malignancies of the lung (Dicke et al, 2005; McDonagh et al, 2012; Yuan et al, 2017). Genetic polymorphism in CYP2A6 is known to lead to the poor or extensive metabolizer (PM or EM) phenotype (Kamataki, 2006; Zanger & Schwab, 2013). An absence of enzyme activity is reported due to the deletion‐type variants, that is, CYP2A6*4B and CYP2A6*4C (Fujieda et al, 2004).…”

Novel DNA Polymerases and Novel Genotoxicity Assays

“…Human CYP enzymes are successfully expressed in Salmonella cells and they are active to metabolize a variety of genotoxic compounds (92). Modulation of genes involved in DNA repair and TLS would substantially aŠect the sensitivity of the tester strains.…”