Steroidogenic cytochrome P450 gene CYP11A1: Functions and regulation

Abstract

Steroids belong to the class of endogenous substrates that are metabolized by cytochromes P450. These steroids are produced in our body, mainly from the adrenals and gonads, and circulate throughout the body in minute amounts to exert their physiological functions. The first and rate-limiting step for the production of all steroids is the conversion of cholesterol into pregnenolone, catalyzed by P450scc, or CYP11A1. Deficiency of CYP11A1 results in adrenal insufficiency that can be lethal when untreated. Hypomorphic expression of Cyp11a1 is less detrimental, but still resulted in decreased stress response in mice. CYP11A1 is expressed mainly in the adrenals and gonads, and to a lesser extent brain, skin, and intestine. Transcription factor NR5A1 controls the expression of Cyp11a1 in the adrenals and testis, whereas NR5A2 controls the expression of Cyp11a1 in the intestine. Both NR5A proteins cooperate with other general factors such as Sp1 and AP1 to activate Cyp11a1 expression in response to the stimulation of cAMP. The cyp11a1 mRNA in zebrafish is also deposited as a maternal transcript for the production of pregnenolone in early embryos. Pregnenolone stabilizes microtubules and promotes embryonic cell migration in zebrafish. Thus, use of the zebrafish model reveals a new function of CYP11A1 during early embryogenesis.