The effects of streptozotocin-induced diabetes and fasting on hepatic cytochrome P-450 enzymes in sexually mature male rats were studied by immunochemical techniques and enzyme assays. The level of cytochrome P-450ac (an acetone/ethanol inducible form), 65 pmol/mg microsomal protein in control rats, increased 4- to 5-fold in diabetic rats and 3- and 5-fold in fasting rats. In contrast, P-450 UT-A (a male specific form) decreased drastically from 295 pmol/mg in the control group to about 10% of this value in diabetic rats and to 50% in fasting rats. P-450 PCN-E (a 16 alpha-cyanopregnenolone/dexamethasone inducible form), on the other hand, decreased from 151 pmol/mg to 38% in diabetic rats and increased 2-fold in fasting rats. These changes were also reflected in catalytic activities using N-nitrosodimethylamine, benzphetamine, and erythromycin as substrates. Slight changes in cytochromes P-450 UT-F, P-450 UT-I and P-450 PB-C were also observed under these conditions, but the biological significance is not known. These results suggest that different mechanisms exist for the regulation of the expression of cytochrome P-450 enzymes in diabetic and fasting rats.