EXPRESSION AND DISTRIBUTION OF CYTOCHROME-P450 ENZYMES IN MALE-RAT KIDNEY - EFFECTS OF ETHANOL, ACETONE AND DIETARY CONDITIONS

Ethanol, acetone, diet and starvation, known modulators of the hepatic cytochrome P450 (CYP)-dependent microsomal monooxygenase system, were assessed for their effects on cytochrome P450 isozyme content and mon ooxygenase activities in the male rat kidney. In acute experiments, ra ts were either treated with acetone, fasted or given a combination of the two treatments. Acetone treatment alone induced CYP2E1-dependent p -nitrophenol hydroxylase activity in kidney microsomes by 8-fold. This was accompanied by a 6-fold increase in CYP2E1 apoprotein as determin ed by Western blot analysis. There was, however, no significant increa se in steady-state levels of CYP2E1 mRNA as measured by Northern blot analysis. Starvation also induced CYP2E1 apoprotein in the kidney and, as has been reported previously in the liver, had a synergistic induc tive effect with acetone. CYP2B and CYP3A apoproteins were also induce d by acetone, starvation and starvation/acetone combinations in the ki dney. Immunohistochemical analysis revealed localization of CYP2E1 and CYP2B principally in the cortex associated with tubular cells. This d istribution was maintained upon starvation/acetone treatment. Two indu ction experiments were performed in which the ethanol was administered as part of a system of total enteral nutrition (TEN). A short-term st udy was conducted in which ethanol was administered for 8 days in two liquid diets oi different composition, and a chronic experiment was pe rformed in which ethanol was administered for 35 days. A diet-independ ent 6-fold increase in CYP2E1 apoprotein was observed in the short-ter m experiment. Expression of CYP3A and CYP2A cross-reactive apoproteins in kidney microsomes appeared to be affected by alterations in diet b ut, were unaffected by ethanol treatment. In the chronic 35-day ethano l exposure experiment, CYP2E1 apoprotein was also elevated 6-fold and this was found to be accompanied by a significant 3-fold increase in C YP2E1 mRNA. In the same study, no ethanol effects were apparent on exp ression of CYP2B and CYP3A apoproteins. Thus, acetone induced a variet y of renal cytochrome P450 forms in addition to CYP2E1, while ethanol appeared to be a much more specific renal CYP2E1 inducer. Furthermore, as reported in the liver, acetone and ethanol appeared to induce CYP2 E1 in the kidney by different mechanisms. (C) 1998 Elsevier Science In c.