o-Methoxy-4-alkylphenols That Form Quinone Methides of Intermediate Reactivity Are the Most Toxic in Rat Liver Slices

• Published in: Chemical research in toxicology 1995-04, Vol.8 (3), p.323-327
• Main Authors: Thompson, David C, Perera, Kumar, Krol, E. S, Bolton, Judy L
• Format: Article
• Language: English
• Subjects: Animals; Anisoles - toxicity; Catalysis; Cytochrome P-450 Enzyme System - metabolism; Glutathione - metabolism; Indolequinones; Indoles - chemical synthesis; Indoles - toxicity; Male; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Phenols - metabolism; Quinones - chemical synthesis; Quinones - toxicity; Rats; Rats, Sprague-Dawley
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx00045a001

The effects of p-alkyl substituents on the relative cytotoxicity of 4-alkyl-2-methoxyphenols were investigated in isolated rat liver slices. The derivatives of 4-alkyl-2-methoxyphenol studied were 4-methyl- (creosol), 4-ethyl-, 4-propyl-, 4-isopropyl-, 4-allyl-2-methoxyphenol (eugenol), as well as 4-allyl-2,6-dimethoxyphenol. The data were correlated with previous microsomal experiments which showed that all of the 4-alkyl-2-methoxyphenols were converted to quinone methides (QMs; 4-methylene-2,5-cyclohexadien-1-ones) via a cytochrome P450-catalyzed process [Bolton, J. L. Comeau, E., and Vukomanovic, V. (1995) Chem.-Biol. Interact., in press]. The present investigation showed little correlation between the rate of QM formation in microsomes and the relative toxicities of the alkylphenols, unless the QMs formed were of similar reactivity. In contrast, a plot of alkylphenol toxicity versus the relative hydrolysis rates of QMs derived from these phenols fit a parabolic equation with a minimum at the data for 4-isopropyl-2-methoxyphenol. These data suggest that in vivo oxidation of phenols to QMs which have lifetimes in the 10 s-10 min range results in cytotoxicity. QMs with reactivities outside this window are less toxic since the electrophile is either too stable for reaction with cellular nucleophiles or too reactive for nucleophilic cellular macromolecules to compete with solvent. These data suggest that a reactivity window exists for QMs which is a primary determinant of the extent of cytotoxic injury caused by these reactive electrophiles.