Studies on the Metabolism of Benzo[a]Pyrene and Dose-Dependent Differences in the Mutagenic Profile of Its Ultimate Carcinogenic Metabolite

Conney, Allan H.; Chang, Richard L.; Jerina, Donald M.; Wei, S.-J. C.

doi:10.3109/03602539409029788

Cited by 133 publications

(86 citation statements)

References 37 publications

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“…The obvious importance and relevance of an association between BaP-DNA adducts and BaPinduced CYP1A1-mediated toxicity, mutagenesis, teratogenesis, and cancer are well known (Pelkonen and Nebert, 1982;Nebert, 1989;Conney et al, 1994;Knize et al, 1999;Miller and Ramos, 2001). Contrary to what was expected, Fig.…”

Section: Major Role Of Cyp1a1 In Detoxication 1231contrasting

confidence: 50%

“…Hundreds of studies performed in vitro and in cell culture have demonstrated clearly that CYP1A1 is involved in the metabolic activation of BaP into reactive intermediates capable of binding to DNA and proteins. Numerous reports have shown that one or more of the reactive intermediates, rather than the nonmetabolized parent compound, is responsible for BaP-mediated toxicity, mutations, cancer, and birth defects (Pelkonen and Nebert, 1982;Conney et al, 1994;Knize et al, 1999;Miller and Ramos, 2001).…”

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confidence: 99%

“…An important and very extensively studied prototype of this class of compounds is benzo [a]pyrene (BaP) (Pelkonen and Nebert, 1982;Conney et al, 1994;Knize et al, 1999;Miller and Ramos, 2001). BaP has been demonstrated to cause carcinogenic, mutagenic, cytotoxic, and teratogenic effects in various species and tissues (Nebert, 1989;Ellard et al, 1991;Conney et al, 1994;Miller and Ramos, 2001).…”

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confidence: 99%

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Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

Uno

Dalton²,

Derkenne³

et al. 2004

Mol Pharmacol

291

263

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The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo [a]pyrene (BaP), to DNA-and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(Ϫ/Ϫ) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(ϩ/ϩ) wild-type mice. At an oral BaP dose of 125 mg/ kg/day, Cyp1a1(Ϫ/Ϫ) mice died within 30 days whereas Cyp1a1(ϩ/ϩ) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(Ϫ/Ϫ) than Cyp1a1(ϩ/ϩ) mice. The cause of death in Cyp1a1(Ϫ/Ϫ) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(Ϫ/Ϫ) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(Ϫ/Ϫ) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(ϩ/ϩ) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.

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Section: Major Role Of Cyp1a1 In Detoxication 1231contrasting

confidence: 50%

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confidence: 99%

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confidence: 99%

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Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

Uno

Dalton²,

Derkenne³

et al. 2004

Mol Pharmacol

291

263

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“…Oxidative phase I metabolism, especially via P450s, was generally believed to be detrimental in any cell type of every vertebrate, including microsomal studies in vitro and studies in cell culture (Conney et al, 1994;Nebert et al, 2004). In contrast, conjugative phase II metabolism was regarded as almost always beneficial Talalay, 2000).…”

Section: Resultsmentioning

confidence: 99%

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

et al. 2013

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Benzo [a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent is found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds, and highways. Cytochrome P450 1 wild-type, Cyp1a2(2/2), Cyp1b1(2/2), or Cyp1a2/1b1(2/2) knockouts, and mice with Cyp1a1 expression deleted in hepatocytes can ingest large oral BaP doses (125 mg/kg/d) without apparent toxicity. Cyp1a1(2/2) and Cyp1a1/1a2(2/2) knockouts and mice with Cyp1a1 expression deleted in gastrointestinal (GI) tract epithelial cells develop immunotoxicity and die within 32 days, indicating that GI tract inducible CYP1A1 is absolutely required for detoxication of oral BaP. Cyp1a1/1b1(2/2) and Cyp1a1/1a2/1b1(2/2) mice are rescued from immunosuppression and early death due to absent metabolic activation of BaP by CYP1B1 in immune cells. Ten-fold lower oral BaP doses result in adenocarcinoma of the proximal small intestine (PSI) in Cyp1a1(2/2) mice; Cyp1a1/1b1(2/2) double-knockout mice show no PSI cancer but develop squamous cell carcinoma of the preputial gland duct (PGD). BaP-metabolizing CYP1B1 in the PSI and CYP3A59 in the PGD are the most likely candidates to participate in tumor initiation in the epithelial cells of these two tissues; oncogenes and tumor-suppressor genes upregulated and downregulated during tumorigenesis are completely different between these tissues. This "oral BaP Cyp1" mouse paradigm represents a powerful teaching tool, showing that gene-environment interactions depend on route-of-administration: the same oral, but not intraperitoneal, BaP exposure leads to dramatic differences in target-organ toxicity and tumor type as a function of dose and Cyp1 genotype.

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“…26) Numerous reports have shown that one or more of the reactive intermediates, rather than the nonmetabolized parent compound, is responsible for B[a]P-mediated mutations and carcinogenesis. 12,28) Expression of CYP1A1 is constitutively nil but is markedly induced in a large number of tissues after induction by PAHs. 29) In addition, constitutive CYP1B1 is extremely low in the liver but is detectable after PAH exposure.…”

Section: Discussionmentioning

confidence: 99%

Preventive Effect of Preinduction of Metallothionein on Mutagenicity Caused by Benzo[a]pyrene

Takaishi

Suzuki

Satoh

et al. 2010

JOURNAL OF HEALTH SCIENCE

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The effect of pretreatment with zinc (Zn) compounds on the mutagenicity of benzo [a]pyrene (B[a]P) was investigated using metallothionein (MT)-I/II null mice. MT-I/II null mice and wild-type mice were subcutaneously administered ZnSO 4 once a day for 2 days and gavaged B[a]P at 24 hr after the last injection of ZnSO 4 . B[a]Pinduced micronucleus frequencies were reduced by Zn pretreatment in the wild-type mice but not in the MT-I/II null mice. Zn administration significantly increased the concentration of MT in the liver and bone marrow cells of wild-type mice, but the statuses of other cellular antioxidants, such as glutathione, catalase and superoxide dismutase, were unchanged. In addition, the activity of a major B[a]P metabolic activation enzyme, cytochrome P450 1A, was unchanged by Zn treatment in both MT-I/II null mice and wild-type mice. These results suggest that Zn pretreatment protects against the mutagenicity of B[a]P through the induction of MT synthesis. The amount of MT produced in animals may determine their sensitivity to B[a]P exposure.

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Studies on the Metabolism of Benzo[a]Pyrene and Dose-Dependent Differences in the Mutagenic Profile of Its Ultimate Carcinogenic Metabolite

Cited by 133 publications

References 37 publications

Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

Preventive Effect of Preinduction of Metallothionein on Mutagenicity Caused by Benzo[a]pyrene

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