Metabolism of Benzo[a]pyrene to trans-7,8-Dihydroxy-7,8-dihydrobenzo[a]pyrene by Recombinant Human Cytochrome P450 1B1 and Purified Liver Epoxide Hydrolase

Shimada, Tsutomu; Gillam, Elizabeth M. J.; Oda, Yoshimitsu; Tsumura, Fujiko; Sutter, Thomas R.; Guengerich, F. Peter; Inoue, Kiyoshi

doi:10.1021/tx990028s

Cited by 147 publications

(105 citation statements)

References 36 publications

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“…CYP1B1 appears to be more active than CYP1A1 in the conversion of a number of PAHs to genotoxic intermediates (269). In the presence of epoxide hydrolase, both CYP1A1 and CYP1B1 catalyze the conversion of the archetypal PAH, benzo[a]pyrene, to its 7,8-dihydrodiol, and both enzymes can in turn metabolically activate this benzo[a]pyrene metabolite to a mutagenic form (269,271,272). Covalent adducts, formed by the reaction of PAH diol epoxide metabolites with guanine in mutational hotspots of critical genes such as that of the p53 tumor suppressor (273,274), may initiate tumorigenesis if not efficiently repaired.…”

Section: Mixtures and Ahr-mediated Effectsmentioning

confidence: 99%

Understanding the human health effects of chemical mixtures.

Carpenter

Arcaro

Spink

2002

Environ Health Perspect

329

198

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Most research on the effects of chemicals on biologic systems is conducted on one chemical at a time. However, in the real world people are exposed to mixtures, not single chemicals. Although various substances may have totally independent actions, in many cases two substances may act at the same site in ways that can be either additive or nonadditive. Many even more complex interactions may occur if two chemicals act at different but related targets. In the extreme case there may be synergistic effects, in which case the effects of two substances together are greater than the sum of either effect alone. In reality, most persons are exposed to many chemicals, not just one or two, and therefore the effects of a chemical mixture are extremely complex and may differ for each mixture depending on the chemical composition. This complexity is a major reason why mixtures have not been well studied. In this review we attempt to illustrate some of the principles and approaches that can be used to study effects of mixtures. By the nature of the state of the science, this discussion is more a presentation of what we do not know than of what we do know about mixtures. We approach the study of mixtures at three levels, using specific examples. First, we discuss several human diseases in relation to a variety of environmental agents believed to influence the development and progression of the disease. We present results of selected cellular and animal studies in which simple mixtures have been investigated. Finally, we discuss some of the effects of mixtures at a molecular level.

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Section: Mixtures and Ahr-mediated Effectsmentioning

confidence: 99%

Understanding the human health effects of chemical mixtures.

Carpenter

Arcaro

Spink

2002

Environ Health Perspect

329

198

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“…In humans P450s most implicated in PAH activation are 1A1, 1B1 (39,40) and the AKRs most involved are (1A1, 1C1-1C4) (20,21,41). These enzymes are differentially expressed and regulated.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography–Mass Spectrometry

Jiang

Gelhaus

Mangal

et al. 2007

Chem. Res. Toxicol.

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Benzo [a]pyrene (B[a]P), a representative polycyclic aromatic hydrocarbon (PAH), is metabolically activated by three enzymatic pathways; by peroxidases (e.g. cytochrome P450-peroxidase) to yield radical cations; by P4501A1/1B1 monoxygenation plus epoxide hydrolase to yield diol-epoxides; and by P4501A1/1B1 monoxygenation, epoxide hydrolase plus aldo-keto reductases (AKRs) to yield o-quinones. In humans, a major exposure site for environmental and tobacco smoke PAH is the lung, however, the profile of B[a]P metabolites formed at this site has not been well characterized. In this study, human bronchoalveolar H358 cells were exposed to B[a]P, and metabolites generated by peroxidase (B[a]P-1,6-and B[a]P-3,6-diones), from cytochrome P4501A1/1B1 monooxygenation (3-hydroxyl-B[a]P, B[a]P-7,8-and 9,10-trans-dihydrodiols, and B[a]P -r-7,t-8,t-9,c-10-tetrahydrotetrol (B[a]P -tetrol-1)), and from AKRs (B[a]P-7,8-dione) were detected and quantified by RP-HPLC-with in line photo-diode array and radiometric detection, and identified by LC-MS. Progress curves showed a lag-phase in the formation of 3-hydroxy-B[a]P, B[a]P-7,8-transdihydrodiol, B[a]P-tetraol-1 and B[a]P-7,8-dione over 24 h. Northern blot analysis showed that B [a]P induced P4501B1 and AKR1C isoforms in H358 cells in a time-dependent manner providing an explanation for the lag-phase. Pretreatment of H358 cells with 10 nM 2,3,7,8-tetrachlorodibenzop-dioxin, (TCDD) eliminated this lag-phase, but did not alter the levels of the individual metabolites observed, suggesting that both B[a]P and TCDD induction ultimately yield the same B[a]P-metabolic profile. The one exception was B[a]P-3,6-dione which was formed without a lag-phase in the absence and presence of TCDD, suggesting that the peroxidase responsible for its formation was neither P4501A1 nor 1B1. Candidate peroxidases that remain include PGH synthases and uninduced P450 isoforms. This study shows that the P4501A1/1B1 and AKR pathways are inducible in human lung cells and that the peroxidase pathway was not. It also provides evidence that each of the pathways of PAH-activation yield their distinctive metabolites in H358 human lung cells and that each pathway may contribute to the carcinogenic process.

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“…There are three major pathways for the activation of B[a]P. In the first pathway, P450 peroxidases catalyze the generation of radical cations (5), which lead to the formation of depurinating adducts and result in G to T transversions (6) (4,7,8) or to B[a]P-7,8-dione by aldo-keto reductases (AKR1A1 and AKR1C1 to -1C4) (9 -11) (Scheme 1).…”

mentioning

confidence: 99%

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Zhang

Jin

Chen

et al. 2011

Journal of Biological Chemistry

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Polycyclic aromatic hydrocarbons (PAH)2 are ubiquitous environmental pollutants that are products of fossil fuel combustion and found in tobacco smoke and are suspect lung carcinogens (1, 2). PAH are considered to be procarcinogens and require metabolic activation to elicit their deleterious effects. Benzo[a]pyrene (B[a]P) is a representative PAH and widely used to study the metabolic activation of PAH (3, 4).There are three major pathways for the activation of B[a]P. In the first pathway, P450 peroxidases catalyze the generation of radical cations (5) PAH o-quinones, produced by AKRs are electrophilic and highly reactive to endogenous nucleophiles. PAH o-quinones can readily form conjugates with cellular thiols to yield and GSH conjugates, leading to their elimination (12,13). PAH o-quinones can also react with DNA to form both stable and depurinating adducts, which may result in mutagenesis (14 -16). PAH o-quinones are also able to undergo nonenzymatic/enzymatic reduction to reform catechols at the expense of NADPH and establish futile redox cycles that amplify the generation of reactive oxygen species (ROS). ROS can cause DNA damage resulting in the formation of 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8-oxo-dGuo) lesions and can contribute to G to T transversions in ras and p53 (17,18). PAH o-quinones were found to be more mutagenic than diol-epoxides in an in vitro p53 mutagenesis assay provided they redox-cycled and a linear correlation was observed

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Metabolism of Benzo[a]pyrene to trans-7,8-Dihydroxy-7,8-dihydrobenzo[a]pyrene by Recombinant Human Cytochrome P450 1B1 and Purified Liver Epoxide Hydrolase

Cited by 147 publications

References 36 publications

Understanding the human health effects of chemical mixtures.

Understanding the human health effects of chemical mixtures.

Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography–Mass Spectrometry

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

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