Benzo[a]pyrene-Induced Toxicity: Paradoxical Protection in Cyp1a1(−/−) Knockout Mice Having Increased Hepatic BaP–DNA Adduct Levels

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

“…This finding is consistent with suggestions of Uno et al (2001; (Uno et al, 2001;Arlt et al, 2008;. Indeed, Uno et al (2001) showed that absence of the Cyp1a1 enzyme protects the intact animal from BaP-mediated liver toxicity and death, by decreasing the formation of large amounts of toxic metabolites, whereas much slower metabolic clearance of BaP in Cyp1a1(-/-) mice leads to greater formation of BaP-DNA adducts. Using the Hepatic P450 Reductase Null (HRN) and the Reductase Conditional Null (RCN) mouse model we also showed that hepatic CYP enzymes appear to be more important for detoxification of BaP in vivo (Arlt et al, 2008;.…”

Benzo(a)pyrene-induced metabolic responses in Manila clam Ruditapes philippinarum by proton nuclear magnetic resonance (1H NMR) based metabolomics

“…The mechanisms of PAHs toxicity are very complex because PAHs can be metabolically activated by Phase I enzymes (e.g., cytochrome p450) to reactive intermediates that bind covalently to nucleic acids and proteins. Moreover, PAHs can induce numerous enzymes involved in activation and detoxification of PAHs via the aromatic hydrocarbon receptor (AHR), and PAHs can affect the expression of multiple other genes by way of both AHR-dependent and AHR-independent mechanisms (Uno et al, 2001;Puga et al, 1992;Hankinson, 1995;Ryu et al, 1996). However, metabolomics can provide an overview on the toxicological effects of PAHs in organisms by characterizing the metabolic responses (biomarkers) without detailed knowledge of the complex biotransformation of PAHs (Lin et al, 2006;Stentiford et al, 2005).…”

“…PAH contamination is of great concern since these compounds are known to be cytotoxic, carcinogenic and mutagenic to various organisms (Uno et al, 2001;Toyooka and Ibuki, have been well-documented (Binelli et al, 2008;Poirier and Beland, 1992;Uno et al, 2001). For example, Poirier and Beland (1992) reported that the carcinogenicity of BaP was attributed to the reaction of BaP metabolites, primarily the diol epoxides, with DNA (Poirier and Beland, 1992).…”

Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

“…CYP1A1/CYP1B1 are ultimately responsible for the monoxygenation of PAH to yield diolepoxides, which form covalent bulky adducts with DNA that lead to mutation (19,20). Paradoxically, studies with CYP1A1 and CYP1B1 knockout mice show that these enzymes protect against benzo[a]pyrene (B[a]P) toxicity because in their absence, diol-epoxide DNA adduct levels are even higher (21)(22)(23). This outcome is evident in human bronchoalveolar (H358) cells where cells induced to express CYP1B1 produced less anti-B[a]P-diol epoxide-N 2 -dGuo adducts than uninduced cells (24).…”