O-METHOXY-4-ALKYLPHENOLS THAT FORM QUINONE METHIDES OF INTERMEDIATE REACTIVITY ARE THE MOST TOXIC IN RAT-LIVER SLICES

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- (c reosol), 4-ethyl-, 4-propyl-, 4-isopropyl-, 4-allyl-2-methoxyphenol (e ugenol), as well as 4-allyl-2,6-dimethoxyphenol. The data were correla ted with previous microsomal experiments which showed that all of the 4-alkyl-2-methoxyphenols were converted to quinone methides (QMs; 4-me thylene-2,5-cyclohexadien-1-ones) via a cytochrome P450-catalyzed proc ess [Bolton, J. L., Comeau, E., and Vukomanovic, V. (1995) Chem.-Biol. Interact., in press]. The present investigation showed little correla tion between the rate of QM formation in microsomes and the relative t oxicities of the alkylphenols, unless the QMs formed were of similar r eactivity. In contrast, a plot of-alkylphenol toxicity versus the rela tive hydrolysis rates of QMs derived from these phenols fit a paraboli c equation with a minimum at the data for 4-isopropyl-2-methoxyphenol. These data suggest that in vivo oxidation of phenols to QMs which hav e lifetimes in the 10 s-10 min range results in cytotoxicity. QMs with reactivities outside this window are less toxic since the electrophil e is either too stable for reaction with cellular nucleophiles or too reactive for nucleophilic cellular macromolecules to compete with solv ent, These data suggest that a reactivity window exists for QMs which is a primary determinant of the extent of cytotoxic injury caused by t hese reactive electrophiles.