Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: relationship to toxicity.
The oxidative metabolism and toxicity of the para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol were studied using male Sprague-Dawley rat liver microsomes and precision-cut liver slices. Reactive intermediates from each compound were trapped using radiolabeled glutathione and were detected and quantified by HPLC. Conjugates were collected and their structures determined by fast atom bombardment mass spectrometry and proton nuclear magnetic resonance. During microsomal incubations each test compound formed monoglutathione conjugates with structures which are consistent with the formation of quinone methide intermediates. In each case the glutathione moiety was attached to the benzylic carbon on the alkyl side chain of the phenol. With ethylphenol, which has a prochiral benzylic carbon, two isomeric conjugates were detected. The rate of formation of the glutathione conjugates in liver slice incubations was 4-isopropylphenol > 4-ethylphenol > 4-methylphenol. This correlated with the toxicity of the three compounds in liver slices. At equimolar concentrations 4-isopropylphenol was the most toxic while 4-methylphenol was the least toxic. Depletion of intracellular glutathione was observed in the presence of each test compound which preceded cell death. Enhancement of cellular thiol levels with N-acetylcysteine protected cells from the toxic effects of all three compounds as did inhibition of cytochrome P450 activity with metyrapone. These results suggest the formation of quinone methide intermediates from three alkylphenols during oxidative metabolism and demonstrate a correlation between the amount of reactive intermediate formed and toxicity observed in liver slices.
Thompson
D C
DC
Department of Medical Pharmacology & Toxicology, Texas A&M University, College Station 77843, USA.
Perera
K
K
London
R
R
D000818:Animals; D001711:Biotransformation; D003408:Cresols / Q000378:metabolism* / Q000633:toxicity; D066298:In Vitro Techniques; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity; D011809:Quinones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003408:Cresols; D045563:Indolequinones; D007211:Indoles; D010636:Phenols; D011809:Quinones; C068040:quinone methide; C028690:4-isopropylphenol; C042291:4-ethylphenol; C077977:cresol