Hormonal Regulation of Cytochrome P450 Enzymes, Cholesterol Side-Chain Cleavage and 17α-Hydroxylase/C17 – 20 Lyase in Leydig Cells1

Testosterone biosynthesis in Leydig cells is dependent on two cytochrome P450 enzymes, cholesterol side-chain cleavage (P450scc) and 17α-hydroxylase/C17–20 lyase (P45017α). The expression of these two enzymes is differentially regulated by LH acting via its second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP), and by specific steroid hormones. P450scc is constitutively expressed in normal mouse Leydig cells and in MA-10 tumor Leydig cells. Chronic cAMP stimulation increases the steady state levels of P450scc mRNA and de novo P450scc protein synthesis. In contrast, cAMP is obligatory for de novo synthesis of P45017α in normal mouse Leydig cells; P45017α synthesis ceases in the absence of luteinizing hormone or cAMP. MA-10 tumor Leydig cells do not express P450(17α) even after treatment with cAMP. The amount of P450(17α) in Leydig cells is negatively regulated by testosterone acting by two distinct mechanisms. At low concentrations, testosterone acts via the androgen receptor to repress cAMP-induced synthesis of P45017α, whereas at high concentrations this steroid increases the rate of degradation of the enzyme by an oxygen-mediated mechanism. Both constitutive and cAMP-induced synthesis of P450scc protein and steady state levels of mRNA are modulated by glucocorticoids. In normal mouse Leydig cells, glucocorticoids repress P450scc synthesis and steady state levels of P450scc mRNA, whereas glucocorticoids stimulate P450scc synthesis and levels of P450scc mRNA in the tumor Leydig cells. Thus regulation of these two cytochrome P450 enzymes in Leydig cells is complex: not only do different factors regulate each enzyme within the same cell, but the same enzyme is regulated by different mechanisms in normal compared to tumor Leydig cells. Many questions remain, including the regulatory mechanisms that determine species and tissue specific expression of P45Oscc and 45017α as well as cAMP-independent expression of P450scc The recent availability of new molecular tools should contribute to a better understanding of the complexity of the regulation of P450 expression in steroidogenic cells.