Comparison of the 17α-Hydroxylase/C17,20-Lyase Activities of Porcine, Guinea Pig and Bovine P450c17 Using Purified Recombinant Fusion Proteins Containing P450c17 Linked to NADPH-P450 Reductase

Shet, Manjunath S.; Fisher, Charles; Tremblay, Yves; Bélanger, Alain; Conley, Alan J; Mason, J. Ian; Estabrook, Ronald W.

doi:10.1080/03602530701468391

Cited by 21 publications

(19 citation statements)

References 75 publications

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“…The capacity of b5 to stimulate P450c17 appears to be well conserved, and the protein conserved enough to cross species. The 17,20-lyase activity of recombinant human P450c17 was stimulated by rat (19) as well as porcine (18) b5, and rat b5 can similarly support the bovine, porcine, and guinea pig P450c17 enzymes (37). The age-related decline in circulating adrenal androgen concentrations (41) is accompanied by a decrease in adrenal b5 expression (42).…”

Section: Discussionmentioning

confidence: 96%

The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) Is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques

Nguyen

Corbin

Pattison³

et al. 2008

Endocrinology

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Adrenarche is thought to be experienced only by humans and some Old World primates despite observed regression of an adrenal fetal zone and establishment of a functional zona reticularis (ZR) in other species like rhesus macaques. Adrenal differentiation remains poorly defined biochemically in nonhuman primates. The present studies defined ZR development in the neonatal rhesus by examining androgen synthetic capacity and factors affecting it in rhesus and marmoset adrenals. Western immunoblots examined expression of 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3beta-hydroxysteroid dehydrogenase (3betaHSD), among other key enzymes. 17,20-lyase activity was quantified in adrenal microsomes, as was the contribution of b5 to 17,20-lyase activity in microsomes and cell transfection experiments with rhesus and marmoset P450c17. Expression of b5 increased from birth to 3 months, and was positively correlated with age and 17,20-lyase activity in the rhesus. Recombinant b5 addition stimulated 17,20-lyase activity to an extent inversely proportional to endogenous levels in adrenal microsomes. Although 3betaHSD expression also increased with age, P450c17, 21-hydroxylase cytochrome P450, and the redox partner, reduced nicotinamide adenine dinucleotide phosphate-cytochrome P450 oxidoreductase, did not; nor did recombinant cytochrome P450 oxidoreductase augment 17,20-lyase activity. Cotransfection with b5 induced a dose-dependent increase in dehydroepiandrosterone synthesis by both nonhuman primate P450c17 enzymes. We conclude that the increase in 17,20-lyase activity characteristic of an adrenarche in rhesus macaques is driven primarily by increased b5 expression, without the need for a decrease in 3betaHSD, as suggested from human studies. The rhesus macaque is a relevant and accessible model for human ZR development and adrenal function.

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Section: Discussionmentioning

confidence: 96%

The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) Is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques

Nguyen

Corbin

Pattison³

et al. 2008

Endocrinology

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“…The central importance of cytochrome b5 in supporting androgen synthesis by P450c17, and its significance as a functional marker of ZR maturation and androgen production (Sakai et al 1993, Yanase et al 1998, is supported by many elegant biochemical studies from a number of laboratories that have demonstrated its effects on recombinant P450c17 protein activity (Katagiri et al 1995, Lee-Robichaud et al 1995, Auchus et al 1998, Brock & Waterman 1999, Soucy & Luu-The 2000, Shet et al 2007). Specifically, cytochrome b5 selectively augments the 17,20-lyase activity of P450c17 that cleaves the pregnane to an androgen in the last committed step.…”

Section: Biochemical Adrenarchementioning

confidence: 90%

Adrenarche in nonhuman primates: the evidence for it and the need to redefine it

Conley¹,

Bernstein²,

Nguyen³

2012

Journal of Endocrinology

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Adrenarche is most commonly defined as a prepubertal increase in circulating adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfo-conjugate (DHEAS). This event is thought to have evolved in humans and some great apes but not in Old World monkeys, perhaps to promote brain development. Whether adrenarche represents a shared, derived developmental event in humans and our closest relatives, adrenal androgen secretion (and its regulation) is of considerable clinical interest. Specifically, adrenal androgens play a significant role in the pathophysiology of polycystic ovarian disease and breast and prostate cancers. Understanding the development of androgen secretion by the human adrenal cortex and identifying a suitable model for its study are therefore of central importance for clinical and evolutionary concerns. This review will examine the evidence for adrenarche in nonhuman primates (NHP) and suggest that a broader definition of this developmental event is needed, including morphological, biochemical, and endocrine criteria. Using such a definition, evidence from recent studies suggests that adrenarche evolved in Old World primates but spans a relatively brief period early in development compared with humans and some great apes. This emphasizes the need for frequent longitudinal sampling in evaluating developmental changes in adrenal androgen secretion as well as the tenuous nature of existing evidence of adrenarche in some species among the great apes. Central to an understanding of the regulation of adrenal androgen production in humans is the recognition of the complex nature of adrenarche and the need for more carefully conducted comparative studies and a broader definition in order to promote investigation among NHP in particular.

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“…Cows and sheep are closer to humans in terms of steroid biosynthesis regulation, yet there are still some limitations. Ovine and bovine CYP17 do show relative delta 4 lyase deficiency yet their CYP17 also has a greater ability to hydroxylate progesterone with even a substrate preference for progesterone over pregnenolone (Estabrook et al 1991, Waterman et al 1993, Shet et al 1994, Swart et al 2003, Shet et al 2007). The expression of an abundance of CYP17 and HSD3B2 in the zona fasciculata still favors cortisol production over corticosterone Bovine (Ishimura and Fujita 1997, ovine Tangalakis et al 1990, Bird et al 1996).…”

Section: Requirements For Adrenal C19 Steroid Productionmentioning

confidence: 99%

Nonhuman primates as models for human adrenal androgen production: Function and dysfunction

Abbott

Bird

2008

Rev Endocr Metab Disord

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The origin of circulating DHEA and adrenal-derived androgens in humans and nonhuman primates is largely distinct from other mammalian species. In humans and many Old world primates, the fetal adrenal gland and adult zona reticularis (ZR) are known to be the source for production of DHEA (and DHEAS) in mg quantities. In spite of similarities there are also some differences. Herein, we take a comparative endocrine approach to the diversity of adrenal androgen biosynthesis and its developmental timing in three primate species to illustrate how understanding such differences may provide unique insight into mechanisms underlying adrenal androgen regulation and its pathophysiology in humans. We contrast the conventional developmental onset of adrenal DHEA biosynthesis at adrenarche in humans with (1) an earlier, peri-partutrition onset of adrenal DHEA synthesis in rhesus macaques (Old World primate) and (2) a more dynamic and reversible onset of adrenal DHEA biosynthesis in female marmosets (New World primate), and further consider these events in terms of the corresponding developmental changes in expression of CYP17, HSD3B2 and CYB5 in the ZR. We also integrate these observations with recently described biochemical characterization of CYP17 cDNA cloned from each of these nonhuman primate species and the corresponding effects of phosphorylation versus CYB5 coexpression on 17,20 lyase versus 17-hydroxylase activity in each case. In addition, female rhesus macaques exposed in utero to exogenous androgen excess, exhibit symptoms of adrenal hyperandrogenism in adult females in a manner reminiscent of that seen in the human condition of PCOS. The possible mechanisms underlying such adrenal hyperandrogenism are further considered in terms of the effects of altered relative expression of CYP17, HSD3B2 and CYB5 as well as the altered signaling responses of various kinases including protein kinase A, or the insulin sensitive PI3-kinase/AKT signaling pathway which may impact on 17,20 lyase activity. We conclude that while the triggers for the onset of ZR function in all three species show clear differences (age, stage of development, social status, gender), there are still common mechanisms driving an increase in DHEA biosynthesis in each case. A full understanding of the mechanisms that control 17,20 lyase function and dysfunction in humans may best be achieved by comparative studies of the endocrine mechanisms controlling adrenal ZR function and dysfunction in these nonhuman primate species.

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Comparison of the 17α-Hydroxylase/C17,20-Lyase Activities of Porcine, Guinea Pig and Bovine P450c17 Using Purified Recombinant Fusion Proteins Containing P450c17 Linked to NADPH-P450 Reductase

Cited by 21 publications

References 75 publications

The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) Is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques

The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) Is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques

Adrenarche in nonhuman primates: the evidence for it and the need to redefine it

Nonhuman primates as models for human adrenal androgen production: Function and dysfunction

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