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Distinct from other nontoxic phenyl- p -phenylenediamine (PPD) quinones, N -(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine-quinone (6PPD-Q) was recently discovered to be regioselectively metabolized to alkyl hydroxylated metabolites (alkyl–OH-6PPD-Q) in rainbow trout. It remains unknown whether the unique alkyl–OH-6PPD-Q contributes to the toxicity of 6PPD-Q. To test this, we herein synthesized chemical standards of alkyl–OH-6PPD-Q isomers and investigated their metabolic formation mechanism and toxicity. The predominant alkyl–OH-6PPD-Q was confirmed to be hydroxylated on the C 4 tertiary carbon (C 4 –OH-6PPD-Q). The formation of C 4 –OH-6PPD-Q was only observed in microsomal but not in cytosolic fractions of rainbow trout ( O. mykiss ) liver S9. A general cytochrome P450 (CYP450) inhibitor fluoxetine inhibited the formation of hydroxylated metabolites of 6PPD-Q, supporting that CYP450 catalyzed the hydroxylation. This well-explained the compound- and regio-selective formation of C 4 –OH-6PPD-Q, due to the weak C–H bond on the C 4 tertiary carbon. Surprisingly, while cytotoxicity was observed for 6PPD-Q and C 3 –OH-6PPD-Q in a coho salmon ( O. kisutch ) embryo (CSE-119) cell line, no toxicity was observed for C 4 –OH-6PPD-Q. To further confirm this under physiologically relevant conditions, we fractionated 6PPD-Q metabolites formed in the liver microsome of rainbow trout. Cytotoxicity was observed for the fraction of 6PPD-Q, but not the fraction of C 4 –OH-6PPD-Q. In summary, this study highlighted the C 4 tertiary carbon as the key moiety for both metabolism and toxicity of 6PPD-Q and confirmed that alkyl hydroxylation is a detoxification pathway for 6PPD-Q.
Nair et al. (Tue,) studied this question.
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