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

Abstract

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.

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

“…Furthermore, considering AAIa was much less cytotoxic and mutagenic than AAI [14,32] , we speculate that the formation of AAIa by CYP1A plays a role in detoxicification of AAI in vivo in contrast to its toxicity in vitro. The discrepant roles of CYP1A in vivo and in vitro have been shown before [33][34][35] and our study supports that CYP1A is cytoprotective rather than cytotoxic in vivo [36] .…”

The relationship between DNA adduct formation by benzo[a]pyrene and expression of its activation enzyme cytochrome P450 1A1 in rat

“…We found however that the levels of dG-N 2 -BPDE adducts in livers of these mice treated with BaP were higher than in WT mice (Arlt et al, 2008;. Therefore, these and other factors such as: (i) detoxification of reactive BaP metabolites by both phase I and phase II enzymes (conjugation), (ii) rate of repair of BaP-DNA adducts, and (iii) BaP-induced expression of genes of enzymes involved in BaP detoxification or in DNA damage response (Uno et al, 2004;, might also influence BaP-DNA adduct levels in vivo. However, the impacts of those factors on BaP-DNA adduct formation in the present study in vivo remain to be explored.…”

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

“…CYP1A1-null mice died within 30 days after oral administration of 125 mg/kg bw benzo [a]pyrene, while wild-type mice did not show any signs of toxicity for 1 year. In addition, benzo [a]pyrene-DNA adduct levels were found to be higher in CYP1A1-null mice than in the wild-type mice (Uno et al, 2004;Nebert, 2005a).…”

“…Recently, Uno et al (2004) showed that CYP1A1 is important in the detoxification and protection against the oral toxicity of benzo [a]pyrene rather than in its metabolic activation in studies using CYP1A1 knockout mice. CYP1A1-null mice died within 30 days after oral administration of 125 mg/kg bw benzo [a]pyrene, while wild-type mice did not show any signs of toxicity for 1 year.…”