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Studies on the Mechanism of Hepatotoxicity of 4-methylphenol (P-Cresol): Effects of Deuterium Labeling and Ring Substitution

Studies on the Mechanism of Hepatotoxicity of 4-methylphenol (P-Cresol): Effects of Deuterium Labeling and Ring Substitution

D C Thompson, K Perera, R London

Chem Biol Interact. 1996 Jun;101(1):1-11.

PMID: 8665615

Abstract:

We recently observed that 4-methylphenol (p-cresol) is toxic to rat liver tissue slices. A possible mechanism involves biotransformation of 4-methylphenol to a reactive quinone methide intermediate which covalently binds to cellular macromolecules and elicits cytotoxicity. In order to obtain further evidence for this proposed mechanism, we studied the effects of deuterium-labeled 4-methylphenol (4-[alpha, alpha, alpha-d3]-methylphenol), and the presence of various ring substituents, on the metabolism and toxicity of 4-methylphenol in precision cut liver slices prepared from male Sprague-Dawley rats. Deuterium-labeled 4-methylphenol was significantly less toxic than the parent compound in rat liver slices (LC50 = 3.36 vs. 1.31 mM, respectively). In addition, the deuterium-labeled compound was metabolized to a reactive intermediate (measured as glutathione conjugate formation) at a slower rate than that of 4-methylphenol in both liver slices and liver microsomal incubations. The presence of electron withdrawing substituents (2-chloro or 2-bromo) markedly enhanced both metabolism and toxicity, with the exception of 2,6-dibromocresol, which was similar to cresol in terms of rate of metabolism and toxicity. Conversely, the presence of electron donating substituents (2-methoxy, 2-methyl or 2,6-dimethyl) diminished metabolism and toxicity. In addition, methylation of the hydroxyl group to form 4-methylanisole, greatly reduced toxicity. These results support the hypothesis that the toxicity of 4-methylphenol is dependent on the formation of a reactive quinone methide intermediate.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP104938	4-Methylanisole		104-93-8	Price

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