Human Liver Microsomes Are Efficient Catalysts of 1,3-Butadiene Oxidation: Evidence for Major Roles by Cytochromes P450 2A6 and 2E1

Duescher, R J; Elfarra, Adnan A.

doi:10.1006/abbi.1994.1246

Cited by 160 publications

(101 citation statements)

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“…191,192 Inhibition of CYP2A6 activity in smokers increased clearance of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) glucuronide metabolite, suggesting a decreased metabolic activation of NNK and a shunting of NNK to detoxifying NNAL pathways. 193 The loss-of-function allele (CYP2A6*4) has been associated with a decreased risk of smoking-related cancers, 184,[194][195][196] whereas enhanced CYP2A6 activity, such as the duplication allele (CYP2A6*1X2), is predicted to increase risk.…”

Section: Other Likely Candidates Involved In Neurotransmitter Systemsmentioning

confidence: 99%

Overview of the pharmacogenomics of cigarette smoking

Tyndale

2007

Pharmacogenomics J

102

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Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.

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Section: Other Likely Candidates Involved In Neurotransmitter Systemsmentioning

confidence: 99%

Overview of the pharmacogenomics of cigarette smoking

Tyndale

2007

Pharmacogenomics J

102

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“…CYP2A6 is also involved in the metabolic activation of aflatoxin B1 (7), 1,3-butadiene (8) and several nitrosamines, including N-nitrosodiethylamine (3). CYP2A6 presents wide individual variability in its expression in different human tissues (3,9).…”

Section: Introductionmentioning

confidence: 99%

Expression of CYP2A3 mRNA and its regulation by 3-methylcholanthrene, pyrazole, and ß-ionone in rat tissues

Ferreira

Aquino

Queiroga

et al. 2003

Braz J Med Biol Res

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Cytochrome P450 (CYP) 2A enzymes are involved in the metabolism of numerous drugs and hormones and activate different carcinogens. Human CYP2A6, mouse CYP2A5 and rat CYP2A3 are orthologous enzymes that present high similarity in their amino acid sequence and share substrate specificities. However, different from the human and mouse enzyme, CYP2A3 is not expressed in the rat liver. There are limited data about expression of CYP2A3 in extrahepatic tissues and its regulation by typical CYP inducers. Therefore, the objective of the present study was to analyze CYP2A3 mRNA expression in different rat tissues by RT-PCR, and to study the influence of 3-methylcholanthrene, pyrazole and ß-ionone treatment on its expression. Male Wistar rats were divided into four groups of 5 rats each, and were treated ip for 4 days with 3-methylcholanthrene (25 mg/kg body weight), pyrazole (150 mg/kg body weight), ß-ionone (1 g/kg body weight), or vehicle. Total RNA was extracted from tissues and CYP2A3 mRNA levels were analyzed by semiquantitative RT-PCR. CYP2A3 mRNA was constitutively expressed in the esophagus, lung and nasal epithelium, but not along the intestine, liver, or kidney. CYP2A3 mRNA levels were increased in the esophagus by treatment with 3-methylcholanthrene and pyrazole (17-and 7-fold, respectively), in lung by pyrazole and ß-ionone (3-and 4-fold, respectively, although not statistically significant), in the distal part of the intestine and kidney by 3-methylcholanthrene and pyrazole, and in the proximal part of the intestine by pyrazole. CYP2A3 mRNA was not induced in nasal epithelium, liver or in the middle part of the intestine. These data show that, in the rat, CYP2A3 is constitutively expressed in several extrahepatic tissues and its regulation occurs through a complex mechanism that is essentially tissue specific.

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“…The metabolic activation of butadiene proceeds by cytochrome P450-mediated oxidation to epoxybutene (29)(30)(31)(32)(33). Cytochrome P4502E1 is the major P450 isozyme for the metabolism of butadiene (32), although P4502A6 can also oxidize butadiene to epoxybutene (34). Epoxybutene is metabolized further by cytochrome P450 to diepoxybutane, and recent studies indicate that both P4502E1 and P4503A4 catalyze this oxidation step (35).…”

Section: Introductionmentioning

confidence: 99%

Biomonitoring of 1,3-butadiene and related compounds.

Osterman-Golkar

Bond²

1996

Environ Health Perspect

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The 1990 Clean Air Act Amendments list several volatile organic chemicals as hazardous air pollutants, including ethylene oxide, butadiene, styrene, and acrylonitrile. The toxicology of many of these compounds shares several common elements such as carcinogenicity in laboratory animals, genotoxicity of the epoxide intermediates, involvement of cytochrome P450 for metabolic activation (except ethylene oxide), and involvement of at least two enzymes for detoxication of the epoxides (e.g., hydrolysis or conjugation with glutathione). These similarities facilitate research strategies for identifying and developing biomarkers of exposure. This article reviews the current knowledge about biomarkers of butadiene. Butadiene is carcinogenic in mice and rats, which raises concern for potential carcinogenicity in humans. Butadiene is metabolized to DNAreactive metabolites, including 1,2-epoxy-3-butene and diepoxybutane. These epoxides are thought to play a critical role in butadiene carcinogenicity. Butadiene and some of its metabolites (e.g., epoxybutene) are volatile. Exhalation of unchanged butadiene and excretion of butadiene metabolites in urine represent major routes of elimination. Therefore, biomonitoring of butadiene exposure could be based on chemical analysis of butadiene in exhaled breath, blood levels of butadiene epoxides, excretion of butadiene metabolites in urine, or adducts of butadiene epoxides with DNA or blood proteins. Mutation induction in specific genes (e.g., HPRT) following butadiene exposure can be potentially used as a biomarker. Excretion of 1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane or the product of epoxybutene with N-7 in guanine in urine, epoxybutene-hemoglobin adducts, and HPRT mutation have been used as biomarkers in recent studies of occupational exposure to butadiene. Data in laboratory animals suggest that diepoxybutane may be a more important genotoxic metabolite than epoxybutene. Biomonitoring methods need to be developed for diepoxybutane and other putative reactive butadiene metabolites. With butadiene and related compounds, the ultimate challenge is to identify useful biomarkers of exposure in which quantitative linkages between exposure and internal dose of the important DNA-reactive metabolites are established. Environ Health Perspect 104(Suppl 5): 907-915 (1996)

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Human Liver Microsomes Are Efficient Catalysts of 1,3-Butadiene Oxidation: Evidence for Major Roles by Cytochromes P450 2A6 and 2E1

Cited by 160 publications

References 0 publications

Overview of the pharmacogenomics of cigarette smoking

Overview of the pharmacogenomics of cigarette smoking

Expression of CYP2A3 mRNA and its regulation by 3-methylcholanthrene, pyrazole, and ß-ionone in rat tissues

Biomonitoring of 1,3-butadiene and related compounds.

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