Gender and gonadal status differences in zona reticularis expression in marmoset monkey adrenals: Cytochrome b5 localization with respect to cytochrome P450 17,20-lyase activity

Biochemical studies suggest that 17,20-lyase activity, and thus efficient synthesis of androgens by human P450c17, requires both reductase and the accessory protein cytochrome b5. Since the human and primate zona reticularis (ZR) secrete androgens, the expression of these proteins, and of 3β-HSD, was investigated by immunocytochemistry in the adrenal cortex of the mature rhesus macaque. Cytochrome b5 expression was restricted to the cells of the ZR which appeared deficient in 3β-HSD. However, both P450c17 and reductase were evident throughout the zona fasciculata. These data provide essential evidence in support of a functional role for cytochrome b5 in the regional control of 17α-hydroxylase and 17,20-lyase activities of P450c17 and thereby adrenal C19 steroid secretion by the primate adrenal gland.

Download Full-text

Plasticity of the zona reticularis in the adult marmoset adrenal cortex: voyages of discovery in the New World

Journal of Endocrinology ◽

10.1677/joe-08-0554 ◽

2009 ◽

Vol 203 (3) ◽

pp. 313-326 ◽

Cited By ~ 19

Author(s):

J Christina Pattison ◽

David H Abbott ◽

Wendy Saltzman ◽

Alan J Conley ◽

Ian M Bird

Keyword(s):

New World ◽

Cytochrome B5 ◽

Cloning And Expression ◽

Adult Males ◽

Amino Acid Sequence Homology ◽

Zona Reticularis ◽

World Primate ◽

Lyase Activity ◽

Gonadal Status ◽

Combined Data

Adrenarche in humans occurs at the age of 5–7 years, yet the process by which dehydroepiandrosterone (DHEA) biosynthesis in the adrenal zona reticularis (ZR) increases so dramatically remains as a matter of debate. One suggestion is that increased DHEA production by P450c17 (CYP17A1 as listed in HUGO Database) in the ZR results from a coincident fall in the expression of HSD3B, which would otherwise compete for pregnenolone substrate. Nonetheless, studies of human and rhesus adrenal show that cytochrome b5 (CYTB5) expression increases in the ZR with DHEA biosynthesis, and cloned human and rhesus P450c17 show selective increases in 17,20-lyase activity in the presence of CYTB5. The marmoset, a New World primate, expresses a fetal zone during development which regresses after birth. Adult males, however, do not develop an obvious functional ZR, while females develop a ZR in a manner that depends on their social/gonadal status. In all social and physiologic states, changes in marmoset ZR function relate directly to changes in the expression of CYTB5. Recent cloning and expression of marmoset P450c17 also show that while amino acid sequence homology is in the order of ∼85% of that found in human and rhesus sequences, and basal lyase activity is low compared with rhesus, all previously described amino acids critical to human 17,20-lyase activity are completely conserved. Furthermore, the 17,20-lyase activity of the marmoset P450c17 clone is dramatically increased by addition of CYTB5. We propose that these combined data from the marmoset model provide further compelling evidence that the control of ZR CYTB5 expression is a key determinant of ZR function.

Download Full-text

The Primate Adrenal Zona Reticularis is Defined by Expression of Cytochrome b5, 17 -hydroxylase/17,20-lyase Cytochrome P450 (P450c17) and NADPH-Cytochrome P450 Reductase (reductase) but not 3 -Hydroxysteroid Dehydrogenase/ 5-4 Isomerase (3 -HSD)

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.84.9.3382 ◽

1999 ◽

Vol 84 (9) ◽

pp. 3382-3385 ◽

Cited By ~ 21

Author(s):

S. Mapes

Keyword(s):

Cytochrome P450 ◽

Cytochrome B5 ◽

Hydroxysteroid Dehydrogenase ◽

Cytochrome P450 Reductase ◽

Zona Reticularis ◽

Nadph Cytochrome ◽

P450 Reductase ◽

Nadph Cytochrome P450 Reductase

Download Full-text

Tight binding of cytochrome b5 to cytochrome P450 17A1 is a critical feature of stimulation of C21 steroid lyase activity and androgen synthesis

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100571 ◽

2021 ◽

Vol 296 ◽

pp. 100571

Author(s):

Donghak Kim ◽

Vitchan Kim ◽

Kevin D. McCarty ◽

F. Peter Guengerich

Keyword(s):

Cytochrome P450 ◽

Cytochrome B5 ◽

Tight Binding ◽

Critical Feature ◽

Androgen Synthesis ◽

Lyase Activity ◽

Stimulation Of

Download Full-text

Morphological adrenarche in rhesus macaques: development of the zona reticularis is concurrent with fetal zone regression in the early neonatal period

Journal of Endocrinology ◽

10.1677/joe-08-0337 ◽

2008 ◽

Vol 199 (3) ◽

pp. 367-378 ◽

Cited By ~ 26

Author(s):

Ann D Nguyen ◽

Samantha M Mapes ◽

C Jo Corbin ◽

Alan J Conley

Keyword(s):

Cytochrome P450 ◽

Rhesus Macaques ◽

Expression Profiles ◽

Cytochrome B5 ◽

Zona Reticularis ◽

Redox Partner ◽

Cytochrome P450 Oxidoreductase ◽

Dense Band ◽

Cytochrome P450 Family ◽

Steroid Dehydrogenase

Human adrenarche is associated with the establishment of a functional zona reticularis (ZR) and increasing secretion of dehydroepiandrosterone (DHEA) in sulfated form (DS). Like most non-human primates, rhesus macaques are not believed to undergo adrenarche, though they clearly establish a functional ZR after birth. However, the origins of the rhesus ZR are not well defined. Therefore, we investigated the zonal development, steroidogenic enzyme expression and morphology of rhesus adrenals from 1 day to 14 months of age. Immunohistochemistry was conducted to determine expression profiles of the steroidogenic enzymes 17α-hydroxylase/17,20-lyase cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2), hydroxy-Δ-5-steroid dehydrogenase, 3β- and steroid Δ-isomerase 2 (HSD3B2), the redox partner NADPH-cytochrome P450 oxidoreductase (CPR), as well as the accessory protein cytochrome b5 (b5), a marker of the primate ZR. The rhesus ZR is mature by 3 months of age based on differentiation of the innermost zone that lacks HSD3B2, but exhibits increased b5 expression during this period. Further, the ZR develops in neonates from a previously described dense band of cells which we show expresses b5, CYP17A1, CPR, and CYP21A2 throughout maturation. The fetal zone (FZ) is distinguished from the ZR by its lack of CYP21A2, and ZR development proceeded as the FZ regressed with two important implications: neither FZ regression nor ZR maturation can be monitored independently by circulating adrenal androgens, and these events must be induced by different factors in rhesus, and likely humans. Collectively these data demonstrate that ZR development begins before birth in the rhesus, proceeding concomitantly with FZ regression post-natally, suggesting that rhesus experiences morphological adrenarche during the first three months of life.

Download Full-text