Chronic ethanol administration to female rats for 3 weeks was associated with a 60% increase in liver microsomal cytochrome P-450 content. This effect was accompanied by a similar increase in microsomal epoxide hydrase activity, in the presence of styrene oxide, and by significant increases in liver glutathione concentration and cytosolic glutathione S-transferase activities. A time-course study showed that the elevation of liver glutathione concentration seen after 3 weeks of ethanol consumption was a transient phenomenon, not observed after prolonged (23 weeks) ethanol intake and preceded, in the first 10-12 days of ethanol administration, by a decrease below control levels. The latter occurred at a time when the cytochrome P-450 content and the activity of glutathione S-transferases reached maximal increases to levels twice as high as those seen from 3 to 23 weeks of ethanol consumption. These observations show that chronic ethanol consumption may thus affect the hepatotoxicity of xenobiotics susceptible to cytochrome P-450-dependent bioactivation by influencing both this pathway and those involved in the inactivation of reactive metabolites. They also suggest that vulnerability of the liver to such hepatotoxins may be influenced by the duration of exposure to ethanol.