Cytochrome P450IIe1: Roles in Nitrosamine Metabolism and Mechanisms of Regulation

Yang, Chung S.; Yoo, Jeong-Sook H.; Ishizaki, Hiroyuki; Hong, Jun-Yan

doi:10.3109/03602539009041082

Cited by 340 publications

(139 citation statements)

References 39 publications

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“…Because CYP2E1 is involved in the metabolism of alcohol and probably in the activation of short-chain N-nitrosamines present in tobacco smoke, beverages, and food Guengerich and Turvy, 1991;Yang et al, 1990), it is conceivable that CYP2E1 genotypes could modify the risk of tobacco-and alcohol-related cancers. This study, as well as previous studies, is based on the assumption that CYP2E1 polymorphisms may affect the level of enzyme expression.…”

Section: Discussionmentioning

confidence: 99%

Role of alcohol dehydrogenase 3 and cytochrome P‐4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

et al. 2000

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Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH 3 and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH 3 genotype was not associated with UAT cancer. In contrast, a 2-fold risk of oral cavity/ pharyngeal (OR ‫؍‬ 2.0, 95% CI 1.0 -3.9) and laryngeal (OR ‫؍‬ 1.8, 95% CI 1.0 -3.5) cancers was observed for carriers of the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/pharyngeal cancer (OR ‫؍‬ 2.6, 95% CI 1.0 -6.6). The effects of ADH 3 or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers (>80 g/day) with the CYP2E1 DraI C allele (OR ‫؍‬ 5.8, 95% CI 1.9 -18.2) or the CYP2E1 RsaI c2 allele (OR ‫؍‬ 7.2, 95% CI 1.4 -38.2) compared with lighter drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings. Int.

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Section: Discussionmentioning

confidence: 99%

Role of alcohol dehydrogenase 3 and cytochrome P‐4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

et al. 2000

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“…From a toxicological point of view, interest in CYP2E1 revolves around the ability of this enzyme to metabolize and activate many toxicologically important compounds such as ethanol, carbon tetrachloride, acetaminophen, benzene, halothane and many other halogenated substrates. Procarcinogens including nitrosamines and azo compounds are effective substrates for CYP2E1 e.g., CYP2E1 is a low Km dimethylnitrosamine demethylase (48). Toxicity by the above compounds is enhanced after induction of CYP2E1 e.g.…”

Section: Cyp2e1 Substratesmentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

641

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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“…3,4 Numerous studies have shown that several cytochrome P450 (CYP) enzymes, particularly cytochrome P4502A6 (CYP2A6) and cytochrome P4502E1 (CYP2E1), catalyze metabolic activation of nitrosamine derivatives, including N-nitroso-dialkyiamines and tobacco-smoke-related nitrosamine. [5][6][7][8] Genetic polymorphisms for CYP2A6 have been described and 2 variant alleles associated with reduced activity have been identified. Variant 1 (CYP2A6*2) and Variant 2 (CYP2A6*3) are the results of amino acid exchanged for wildtype (CYP2A6*1).…”

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confidence: 99%

“…6 CYP2E1 participated in the metabolic activation of various N-nitrosamines, including a potent tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 8,10 Several recent reports have investigated the role of CYP2A6 genetic polymorphisms in tobacco dependence and lung cancer risk, with conflicting results. [11][12][13][14][15] Less is known, however, about the role of CYP2A6 polymorphic enzymes in gastric cancer.…”

mentioning

confidence: 99%

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

Tsukino

Kuroda

Qiu

et al. 2002

Intl Journal of Cancer

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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. Although gastric cancer incidence has fallen markedly over the past 50 years in industrialized nations, it remains the second leading cause of cancer death in Japan. Epidemiological and experimental evidence have indicated that excess salt intake, which promotes cell replication, increases gastric cancer risk. 1,2 There is considerable evidence to support the view that carcinogenic N-nitrosamine derivatives are important factors in human cancer, including gastric cancer. The chemical mechanisms of carcinogenesis by these nitrosamines in humans are therefore of considerable interest. 3,4 Numerous studies have shown that several cytochrome P450 (CYP) enzymes, particularly cytochrome P4502A6 (CYP2A6) and cytochrome P4502E1 (CYP2E1), catalyze metabolic activation of nitrosamine derivatives, including N-nitroso-dialkyiamines and tobacco-smoke-related nitrosamine. [5][6][7][8] Genetic polymorphisms for CYP2A6 have been described and 2 variant alleles associated with reduced activity have been identified. Variant 1 (CYP2A6*2) and Variant 2 (CYP2A6*3) are the results of amino acid exchanged for wildtype (CYP2A6*1). Recently, Kitagawa et al. 9 revealed that a novel deletion genotype variant of the CYP2A6 gene was one of the major polymorphic genes in Japanese lacking CYP2A6 activity.In addition, CYP2E1 represents a major CYP isoform in the human liver and is also expressed in extrahepatic tissue. This enzyme can be induced by certain chemicals, such as ethanol and large interindividual variations have been observed, suggesting that the variation may be due to genetic polymorphism. It was reported that RsaI polymorphism, which is located in the 5Ј-flanking region of CYP2E1 gene, has been shown to be associated with the transcriptional regulation of gene expression, resulting in different expression levels of the CYP2E1 mRNA. 6 CYP2E1 participated in the metabolic activation of various N-nitrosamines, including a potent tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 8,10 Several recent reports have investigated the role of CYP2A6 genetic polymorphisms in tobacco dependence and lung cancer risk, with conflicting results. [11][12][13][14][15] Less ...

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Cytochrome P450IIe1: Roles in Nitrosamine Metabolism and Mechanisms of Regulation

Cited by 340 publications

References 39 publications

Role of alcohol dehydrogenase 3 and cytochrome P‐4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

Role of alcohol dehydrogenase 3 and cytochrome P‐4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

CYP2E1 and oxidative liver injury by alcohol

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

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