Abstract
3-Aminobenzanthrone (3-ABA) is a human metabolite of carcinogenic 3-nitrobenzanthrone (3-NBA), which occurs in diesel exhaust and air pollution. Understanding which cytochrome P450 (CYP) enzymes are involved in metabolic activation and/or detoxication of this toxicant is important in the assessment of an individual's susceptibility to this substance. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 3-ABA and to examine the metabolites formed during such an oxidation. The metabolites formed by CYPs in rat hepatic microsomes were separated by high performance liquid chromatography (HPLC). 3-ABA is oxidized by these enzymes to three metabolites, which were separated by HPLC as distinguish product peaks. Using co-chromatography with synthetic standards, two of them were identified to be oxidative metabolites of 3-ABA, N-hydroxy-3-ABA and 3-NBA. The structure of another 3-ABA metabolite remains to be characterized. To define the role of rat hepatic CYP enzymes in metabolism of 3-ABA, we investigated the modulation of its oxidation using different inducers of CYPs for treatment of rats to enrich the liver microsomes with individual CYPs. Based on these studies, we attribute most of 3-ABA oxidation in rat hepatic microsomes to CYP2B, followed by CYP1A, although a role of other hepatic CYPs cannot be ruled out. Inhibition of 3-ABA oxidation by selective inhibitors of individual CYPs, supported this finding.
Highlights
3-Aminobenzanthrone (3-ABA, Figure 1) is the reductive metabolite of the carcinogenic environmental pollutant, nitroketone 3-nitrobenzanthrone (3-nitro-7H-benz[de] anthracen-7-one, 3-NBA, Figure 1) (Hansen et al, 2007; Svobodová et al, 2007)
The metabolites formed by cytochrome P450 (CYP) in rat hepatic microsomes were separated by high performance liquid chromatography (HPLC). 3-ABA is oxidized by these enzymes to three metabolites, which were separated by HPLC as distinguish product peaks
To define the role of rat hepatic CYP enzymes in metabolism of 3-ABA, we investigated the modulation of its oxidation using different inducers of CYPs for treatment of rats to enrich the liver microsomes with individual CYPs
Summary
3-Aminobenzanthrone (3-ABA, Figure 1) is the reductive metabolite of the carcinogenic environmental pollutant, nitroketone 3-nitrobenzanthrone (3-nitro-7H-benz[de] anthracen-7-one, 3-NBA, Figure 1) (Hansen et al, 2007; Svobodová et al, 2007). Even though the epidemiological study on the toxicity of 3-ABA has not yet been evaluated, formation of DNA adducts by this reductive metabolite of 3-NBA in vitro and in vivo in rodents inducing these transversion mutations indicates its potential genotoxicity. We have found that cytochromes P450 (CYP) 1A1 and 1A2 are essential for 3-ABA oxidative activation in human and rat livers, forming the same DNA adducts that are formed in vivo by 3-ABA or 3-NBA (Arlt et al, 2004b). Previous results indicate that besides microsomal CYP enzymes cytosolic peroxidases might play a role in the oxidative activation of 3-ABA, mainly in extrahepatic tissues such as kidneys and lungs (Arlt et al, 2006a, Stiborová et al, 2006; 2008). The selective inhibitors of individual CYP enzymes were utilized to identify the most important enzymes oxidizing 3-ABA
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