The inhibition of steroid 6 β-hydroxylase activity by anhydroerythromycin, an acid breakdown product of erythromycin, has been studied and compared to the effects of erythromycin using liver microsomes from control and dexamethasone pretreated rats and human liver microsomes. Both anhydroerythromycin and erythromycin were found to be demethylated, thus both fulfil the prerequisites for possible metabolite-cytochrome P450 complex formation. The formation of a metabolite-cytochrome P450 complex was demonstrated for anhydroerythromycin by preincubating NADPH fortified microsomes with anhydroerythromycin. This complex formation could be reversed by incubating the microsomes in 50 μM potassium ferricyanide. Anhydroerythromycin was a more potent inhibitor of androst-4-ene-3,17-dione (androstenedione) 6 β-hydroxylation than erythromycin. Kinetic analysis shows that there are probably two cytochromes P450 involved in androstenedione 6 β-hydroxylation in control rat microsomes both of which are inhibited by anhydroerythromycin. There are at least two forms of cytochrome P450 responsible for androstenedione 6 β-hydroxylation in microsomes from dexamethasone pretreated rats but only the high affinity form is inhibited by anhydroerythromycin. "Atypical" kinetics were observed in human microsomes but inhibition of androstenedione 6 β-hydroxylation was observed with 5 μM anhydroerythromycin at all androstenedione concentrations used. Inconsistencies have been observed in the literature with respect to clinical interactions observed with erythromycin. Since anhydroerythromycin appears to be a more potent inhibitor of androstenedione 6 β-hydroxylation than erythromycin, we speculate that the variable blood levels of anhydroerythromycin found after dosing with erythromycin may explain these discrepancies. © 1991.
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