The Steroid Hormone Biosynthesis Pathway as a Target for Endocrine-Disrupting Chemicals

Cytochrome P450 enzymes catalyze the degradation of drugs and xenobiotics, but also catalyze a wide variety of biosynthetic processes, including most steps in steroidogenesis. The catalytic rate of a P450 enzyme is determined in large part by the rate of electron transfer from its redox partners. Type I P450 enzymes, found in mitochondria, receive electrons from reduced nicotinamide adenine dinucleotide (NADPH) via the intermediacy of two proteins-ferredoxin reductase (a flavoprotein) and ferredoxin (an iron/sulfur protein). Type I P450 enzymes include the cholesterol side-chain cleavage enzyme (P450scc), the two isozymes of 11-hydroxylase (P450c11beta and P450c11AS), and several vitamin D-metabolizing enzymes. Disorders of these enzymes, but not of the two redox partners, have been described. Type II P450 enzymes, found in the endoplasmic reticulum, receive electrons from NADPH via P450 oxidoreductase (POR), which contains two flavin moieties. Steroidogenic Type II P450 enzymes include 17alpha-hydroxylase/17,20 lyase (P450c17), 21-hydroxylase (P450c21), and aromatase (P450aro). All P450 enzymes catalyze multiple reactions, but P450c17 appears to be unique in that the ratio of its activities is regulated at a posttranslational level. Three factors can increase the degree of 17,20 lyase activity relative to the 17alpha-hydroxylase activity by increasing electron flow from POR: a high molar ratio of POR to P450c17, serine phosphorylation of P450c17, and the presence of cytochrome b(5), acting as an allosteric factor to promote the interaction of POR with P450c17. POR is required for the activity of all 50 human Type II P450 enzymes, and ablation of the Por gene in mice causes embryonic lethality. Nevertheless, mutation of the human POR gene is compatible with life, causing multiple steroidogenic defects and a skeletal dysplasia called Antley-Bixler syndrome.

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Minireview: Regulation of Steroidogenesis by Electron Transfer

Background Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited. Scope of review This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions. Major conclusions Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.

Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies.

CYP17 inhibitors for prostate cancer therapy

Adrenarche is characterized by the increase in adrenal androgen production, namely dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that occurs around 6 years of age. These steroids are secreted by the zona reticularis (ZR) of the adrenal gland. This is associated with pubarche or the increase in androgen-dependent hair growth at the time of puberty. The increase in adrenal androgen production can be explained by the increase in the expression of DHEA-synthesizing steroidogenic enzymes in the ZR. Adrenarche is an event independent of gonadarche and is found only in humans and select nonhuman primates. Although numerous prenatal and postnatal factors are important in the onset of adrenarche, a specific adrenal cortical androgen-stimulating hormone has not been identified. Evidence also exists for a role for adrenarche in behavior, skeletal maturation, and postpubertal well-being. Adrenarche is influenced by sex and race, and some of this variation may be related to the insulin and insulin-like growth factor (IGF) signaling pathways. In addition, children with premature and exaggerated adrenarche may be predisposed to certain diseases later in life.

The rise in adrenal androgen biosynthesis: adrenarche.

Androgens are an integral part of human physiology. The de novo production of androgens is generally limited to the adrenal cortex and the gonads. Androgen synthesis by these steroidogenic tissues requires the bifunctional enzyme cytochrome P450c17, which catalyzes both 17 hydroxylase and 17,20 lyase activities. 17,20-lyase activity is relevant to the regulation of androgen production, and is allosterically modulated through the action of an accessory protein, cytochrome b5 (CytB5). Our objective was to determine the cellular localization of P450c17 and CytB5 in androgen-synthesizing tissues of the human. Immunohistochemical analyses of P450c17 and CytB5 were performed on fetal and adult human adrenals, ovaries, and testes. In the fetal adrenal, CytB5 and P450c17 were both found in the cells of the fetal zone, but not in the neocortex. In the adult adrenal, the zona fasciculata was immunoreactive for P450c17 only, whereas the zona reticularis was immunopositive for both P450c17 and CytB5. In the adult gonads, P450c17 and CytB5 were colocalized in the Leydig cells of the testis, theca interna cells of the follicle, theca lutein cells, and isolated cell clusters in the ovarian stroma. Whereas P450c17 and CytB5 were colocalized in the Leydig cells of the fetal testes, there was no immunostaining for either in the midgestational fetal ovary. Our findings of colocalization of CytB5 and P450c17 are strongly supportive of the view that CytB5 plays an important role in the regulation of the androgen biosynthetic pathway in the fetal and adult human.

Colocalization of P450c17 and Cytochrome b5 in Androgen-Synthesizing Tissues of the Human

Context: Aging in humans is characterized by a selective decline in circulating levels of adrenal androgens. The results of in vivo studies are suggestive of reduced adrenal 17,20-lyase activity in aging men and women. Objective: We sought to determine whether there are changes in the distribution and/or expression of cytochrome B5 (CytB5), an accessory protein important in the regulation of 17,20-lyase activity, in the adrenals of aging humans. Design: Comparison between younger and older adrenal glands. Setting: The study was conducted in a University Center. Patients or Other Participants: Adrenal glands obtained at autopsy after sudden death as a result of trauma from 46 young (age 20–40 yr) and 26 older (age 50–91 yr) humans were obtained and fixed within 24 h postmortem. Interventions: Paraffin sections were stained with hematoxylin and eosin and also were subjected to immunohistochemical staining for CytB5. All sections were quantitatively evaluated using an image capture and analysis program and q...

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Effects of aging on cytochrome b5 expression in the human adrenal gland.

Macrophage migration inhibitory factor (MIF) has been found to be widely expressed in many cell types throughout the body and appears to play several physiologic roles. We sought to determine the expression and cellular distribution of MIF in human fetal (HFA) and adult (HAA) adrenals. A single band of approximately 0.8 kb was revealed by northern blot hybridization using cDNA probes for MIF in total RNA extracts of both HFA and HAA tissues. Immunohistochemical analysis showed strong immunostaining for MIF in the broad fetal zone of the HFA and in both the zona glomerulosa and zona reticularis of HAA. The cells of the zona fasciculata of the HAA and of the neocortex of the HFA were only minimally, if at all, immunopositive for MIF and medullary elements were consistently negative for MIF. These results are indicative of local production of MIF in adrenocortical cells during intrauterine development and also in adulthood. The role of MIF in cortical cells of the human adrenal gland remains to be determined.

https://iubmb.onlinelibrary.wiley.com/doi/pdf/10.1080/1521654031000106672

Ming Jian

Papers

Colocalization of P450c17 and Cytochrome b5 in Androgen-Synthesizing Tissues of the Human

Effects of aging on cytochrome b5 expression in the human adrenal gland.

Macrophage migration inhibitory factor is a constitutively expressed cytokine in the human adrenal gland.