Effects of ischemia on drug-metabolizing microsomal enzymes in rat liver

The activities of some enzymes and the content of some coenzymes associated with membranes of the endoplasmic reticulum are affected by ischemia in a way which is progressive with the duration of ischemia and selective for the various enzymes. Aminopyrine demethylation and aniline hydroxylation are strongly inhibited; cytochrome P-450 content decreases, though with a different pattern; NADPH- and NADH-cytochrome c reductases and cytochrome b5 are unchanged; NAD(P)+ glycohydrolase is only slightly reduced. In the microsomal enzyme systems which catalyze drug metabolism the step affected by ischemia seems to be at the level of the hydroxylating enzymes proper or at the site of coupling between these enzymes and the rest of the pathway. Phenobarbital pretreatment exerts a marked protective effect on the decay of induced aminopyrine demethylase and aniline hydroxylase and on the content of newly formed cytochrome P-450. Differences in turnover and/or in location and stability within the membranes of these enzymes and coenzymes are discussed as possible causes of the differential damage caused by ischemia. Increased oxidation of NADH and NADPH added to microsomal preparations from ischemic livers is another sign of disturbed function which can be tentatively ascribed to some as yet undefined biophysical change of the microsomal membranes.