Novel activities of CYP11A1 and their potential physiological significance

Abstract

CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Δ7steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites. This article is part of a special issue entitled ‘SI: Steroid/Sterol signaling’.

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…Over 12 years we have documented the existence of new pathways of vitamin D3 metabolism started by the action of CYP11A1 and further modified by the actions of CYP27B1, CYP27A1, CYP24A1 and CYP3A4, generating at least 21 hydroxymetabolites with additional ones still to be experimentally defined (Table 1) [43, 50]. At least 13 of them are endogenously produced [72].…”

“…However, the expression of CYP11A1 in peripheral tissues, albeit at low levels, has now been documented [43] and alternative substrates to cholesterol have been identified experimentally, such as 7DHC, vitamins D2 and D3, ergosterol and lumisterol [44–49]. Additionally, the possibility of other sterol/secosteroidal compounds serving as substrates has been predicted theoretically based on molecular modeling [50]. …”

Metabolism of 20-hydroxyvitamin D3 and 20,23-dihydroxyvitamin D3 by rat and human CYP24A1

“…It has been established in the last decade that CYP11A1 (also known as cytochrome P450scc) can metabolize vitamin D3 to produce many novel mono- and poly-hydroxyvitamin D metabolites, the major ones being 20 S -hydroxyvitamin D3 [20(OH)D3] and 20 S ,23-dihydroxyvitamin D3 [20,23(OH) 2 D3] [8–18]. This pathway was initially elucidated from in vitro studies with purified bovine CYP11A1, and more recently has been demonstrated to occur in keratinocyte cell cultures and in fragments of adrenal glands and human placenta incubated with vitamin D3 [16, 18, 19].…”

“…This pathway was initially elucidated from in vitro studies with purified bovine CYP11A1, and more recently has been demonstrated to occur in keratinocyte cell cultures and in fragments of adrenal glands and human placenta incubated with vitamin D3 [16, 18, 19]. Most recently, 20(OH)D3 and 20,23(OH) 2 D3 have been detected at relative levels similar to the classical 25(OH)D3 and 1,25(OH) 2 D3 in human epidermal tissue [20], confirming their production in vivo .…”

Metabolism of Oral Turinabol by Human Steroid Hormone-Synthesizing Cytochrome P450 Enzymes

“…Steroidogenesis is initiated by CYP11A1, which cleaves the side chain of cholesterol, thereby producing pregnenolone, the common precursor for all steroid hormones. In addition, CYP11A1 can convert a variety of other sterol derivatives, as well as vitamins D 2 and D 3 (Slominski et al, 2015) and a set of endogenous steroid intermediates (Mosa et al, 2015). CYP21A2 generates the substrates for gluco-and mineralocorticoid biosynthesis by its 21-hydroxylase activity.…”