Lack of relationship between debrisoquine 4-hydroxylation and other cytochrome P-450 dependent reactions in rat and human liver.

The effect of various inhibitors and inducers of cytochrome P-450 on the activity of microsomal debrisoquine 4-hydroxylation (DQH) was investigated in rat liver. DQH was strongly inhibited by SKF 525-A, 7,8-benzoflavone, and metyrapone. Pretreatment of animals with common inducers, such as phenobarbital, 3-methylcholanthrene, the commercial PCB mixture, Clophen A-50, dexamethasone and pregenenolone-16 alpha-carbonitrile did not lead to induction of DQH, while most reference reactions, i.e. aldrin epoxidation, ethylmorphine demethylation, and benzo(a)-pyrene hydroxylation were induced under these conditions. DQH likewise was not induced by pretreatment of animals with the enzyme substrate DQ. The relationship between DQH and other cytochrome P-450 functions was also studied in untreated animals. Both genders of Wistar rats exhibited similar rates of DQH, but different activities of the reference reactions. DQH activity in Wistar females however, was 10 times higher than in females of the DA-strain, whereas the reference activities were similar in both strains. The studies were also extended to human liver. DQH activity in homogenates of various biopsy samples was neither correlated to the activity of aldrin epoxidation nor to AHH activity. The results indicate that DQH in the rat and in man reflects the activity of a cytochrome P-450 species not related to various other known cytochrome P-450 functions.