The developmental increase in adrenocortical 17, 20-lyase activity (biochemical adrenarche) is driven primarily by increasing cytochrome b5 in neonatal rhesus macaques

Ann D. Nguyen, C. Jo Corbin, J. Christina Pattison, Ian M. Bird, Alan J Conley

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 17α-hydroxylase/17, 20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3β-hydroxysteroid dehydrogenase (3βHSD), 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 3βHSD 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. Co-transfection 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 3βHSD, as suggested from human studies. The rhesus macaque is a relevant and accessible model for human ZR development and adrenal function.

Original languageEnglish (US)
Pages (from-to)1748-1756
Number of pages9
JournalEndocrinology
Volume150
Issue number4
DOIs
StatePublished - Apr 2009

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Adrenarche
Steroid 17-alpha-Hydroxylase
Cytochromes b5
Macaca mulatta
3-Hydroxysteroid Dehydrogenases
Zona Reticularis
Cytochrome P-450 Enzyme System
Microsomes
Primates
Callithrix
Transfection
Oxidoreductases
Testosterone Congeners
Steroid 21-Hydroxylase
Dehydroepiandrosterone
Enzymes
Mixed Function Oxygenases
NADP
Oxidation-Reduction
Western Blotting

ASJC Scopus subject areas

  • Endocrinology

Cite this

The developmental increase in adrenocortical 17, 20-lyase activity (biochemical adrenarche) is driven primarily by increasing cytochrome b5 in neonatal rhesus macaques. / Nguyen, Ann D.; Corbin, C. Jo; Pattison, J. Christina; Bird, Ian M.; Conley, Alan J.

In: Endocrinology, Vol. 150, No. 4, 04.2009, p. 1748-1756.

Research output: Contribution to journalArticle

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abstract = "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 17α-hydroxylase/17, 20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3β-hydroxysteroid dehydrogenase (3βHSD), 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 3βHSD 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. Co-transfection 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 3βHSD, 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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