NITRIC-OXIDE FORMATION DURING THE CYTOCHROME P-450-DEPENDENT REDUCTIVE METABOLISM OF 18-NITRO-OXYANDROSTENEDIONE

18-Nitro-oxyandrostenedione (18-ONO(2)A), a potential mechanism-based inhibitor of the last steps of aldosterone biosynthesis, is well recog nized by different cytochrome P-450s, which are able to metabolize it reductively into nitric oxide (NO) and 18-hydroxyandrostenedione. Rat liver microsomal P-450s are able to carry out this reaction with incre ased efficiency under anaerobic conditions. P-450 3A isozymes induced upon treatment of rats with dexamethasone or troleandomycin were best able to bind and metabolize 18-ONO(2)A. This reaction was shown to occ ur in the presence of dioxygen as well, suggesting that it may be of p hysiological relevance. The formation of NO was detected as a transien t P-450-Fe(II)NO complex by UV-visible and EPR spectroscopy. In additi on, steroidogenic tissues containing cytochrome P-450s such as bovine adrenal mitochondria or human placental microsomes also were capable o f binding and metabolizing 18-ONO(2)A as judged by the formation of an Fe(ll)NO complex. This recognition of a steroid nitrate, a potential antialdosterone and its subsequent metabolism under reductive conditio ns to generate NO both in hepatic and steroidogenic tissues, can be of pharmacological; interest, because NO has been demonstrated to modula te steroidogenesis in addition to other processes such as vascular rel axation, neurotransmission or cytostasis. A nitrate derivative of a st eroid could perhaps act as a vectorized NO precursor in which the ster oid moiety is targeted specifically to steroid receptors or steroidoge nic tissues, thus leading to localized NO liberation.