Cresol isomers: comparison of toxic potency in rat liver slices.
A comparison of the toxicity of cresol isomers (o-, m-, and p-methylphenol) was carried out using precision-cut rat liver slices as a test system. At equimolar concentrations p-cresol was the most toxic isomer. A 5- to 10-fold higher concentration of either the o- or m-isomers was required to observe the same degree of cell killing as p-cresol. The toxicity of p-cresol was inhibited by the thiol precursor N-acetylcysteine and was enhanced by pretreatment of liver slices with diethyl maleate to deplete glutathione. These treatments, however, had little effect on either o- or m-cresol toxicity. p-Cresol rapidly depleted intracellular glutathione levels, while the o- and m-isomers depleted glutathione to a lesser extent. [14C]p-cresol was metabolized to a reactive intermediate which covalently bound to slice protein and was inhibited by N-acetylcysteine. In microsomal incubations covalent binding of [14C]p-cresol metabolites was also observed. This binding was inhibited by glutathione and resulted in the formation of a glutathione conjugate. In the absence of glutathione, p-hydroxybenzyl alcohol was the major microsomal metabolite formed from p-cresol, but this compound was not toxic to liver slices at a concentration of 2 mM. These results demonstrate that p-cresol is the most toxic cresol isomer in rat liver tissue and that its toxicity is dependent on the formation of a reactive intermediate. The results also suggest that the mechanism(s) of toxicity of the o- and m-isomers may differ from that of p-cresol.
Thompson
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Department of Medical Pharmacology & Toxicology, College of Medicine, Texas A&M University, College Station 77843-1114.
Perera
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Fisher
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Brendel
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D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001592:Benzyl Alcohols / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003408:Cresols / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001592:Benzyl Alcohols; D003408:Cresols; C018966:4-hydroxybenzyl alcohol; C032538:4-cresol; D005978:Glutathione; C042041:3-cresol; D000111:Acetylcysteine; C034047:2-cresol