Nitric Oxide, Cytochromes P450, and Sexual Steroid Hormones

The discovery of mammalian nitric oxide (NO-) synthesis from I-ar ginine has led to profound increases in our understanding of basic physiological and pathophysiological processes. This understanding has been achieved by major advances in several areas. Three major ni tric oxide synthase (NOS) isoforms have been identified at the protein and gene level and their specific tissue localization has been linked to processes subject to regulation by NO-. The molecular basis for the di verse effects of NO- on cell function has been shown to derive from its chemical reactivity with oxygen-containing species and both heme and non-heme iron-dependent enzymes. The potential regulation of heme dependent enzymes such as cytochromes P450, guanylate cyclase, cy clooxygenase, and mitochondrial cytochrome oxidase continues to emerge as a key area in NO- research. In addition, it has become clear that the expression of NOS isoforms and NO- release from cells is subject to regulation by sexual steroids and that, in tum, NO- has the potential to regulate steroid biosynthesis via inhibition of cytochromes P450 involved in steroidogenesis. These recent observations on interactions between the NO-/NOS and cytochrome P450/sexual steroid pathways have important implica tions for understanding fundamental mechanisms involved in endocri nological processes. They are also likely to lead to novel insights and novel therapeutic approaches for the management of pathophysiologi cal conditions associated with alterations in sexual steroid hormones.