Studies on the mechanism of hepatotoxicity of 4-methylphenol (p-cresol): effects of deuterium labeling and ring substitution.
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.
Thompson
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Department of Medical Pharmacology & Toxicology, College of Medicine, Texas A&M University Health Sciences Center, College Station 77843-1114, USA. dcthompson@tamu.edu
Perera
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London
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D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003408:Cresols / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity*; D003903:Deuterium; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D003408:Cresols; C032538:4-cresol; D003903:Deuterium; D005978:Glutathione; D011188:Potassium