Impairment of CYP3A4 capacity in patients receiving danazol therapy: examination on oxidative cortisol metabolism

Danazol, a synthetic androgen, is widely used to treat endometriosis and cystic breast disease. We have previously demonstrated that danazol has inhibitory effects on hepatic microsomal cytochrome P450 (P450) system in vitro using several compounds as substrates for enzyme reactions [1]. However, P450 comprises a number of isoforms with varying substrate specificity. CYP3A4 is a major P450 subfamily in humans, accounting for up to 50 % of the total P450 content constitutively expressed in the liver and gut. It is well known that CYP3A4 is responsible for biotransformation of many categories of drugs used in clinical practice, environmental chemicals and important endogenous steroid hormones [2]. Therefore, impairment of CYP3A4 activity can lead to potential drug-interactions and hormonal imbalances due to metabolic disturbance. Although several assay systems have been developed to evaluate CYP3A4 capacity, most of these systems require the administration of exogenous probes. However, it is known that oxidative metabolic conversion of endogenous cortisol to 6β-hydroxycortisol (6β-OHF) is exclusively mediated by CYP3A4. The present study is a preliminary examination of the inhibitory effect of danazol on cortisol 6β-hydroxylation as an index of CYP3A4 activity in humans. The metabolic capacity of cortisol 6β-hydroxylation was evaluated by the urinary excretion ratio of 6β-OHF to cortisol and the ratio of 6β-OHF to 17-hydroxycorticosteroids (17-OHCS), which serves as a non-invasive method involving urine collection only [3] [4].

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