The Role of Cytochrome b5 in the Biosynthesis of Androgens by Human P450c17

Katagiri, Masatoshi; Kagawa, Norio; Waterman, Michael R.

doi:10.1006/abbi.1995.1173

Cited by 223 publications

(135 citation statements)

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“…Whereas CYP17 isoforms from various species all 17 α -hydroxylate progesterone and pregnenolone with comparable efficiencies, the rates of the 17,20-lyase reactions can be very different for the two 17-hydroxysteroids. Human CYP17, as well as CYP17 from sheep, cow and other primates, executes the 17,20-lyase reaction efficiently only with 17 α -hydroxypregnenolone (the ∆ 5 -pathway) (Katagiri et al ., 1995; Immunohistochemistry for 3βHSD in an adrenal gland at age 9 years. Immunoreactivity of 3βHSD was marked in the zona glomerulosa and fasciculata but was almost negative in the zona reticularis.…”

Section: Cyp11a (Cytochrome P450scc; Side-chain Cleavage Enzyme)mentioning

confidence: 99%

“…Hall and colleagues were the first to show that addition of purified b 5 to the reconstituted CYP17 assay system selectively and dramatically enhanced the 17,20-lyase activity (Onoda & Hall, 1982). This effect of b 5 has been seen with CYP17 from many sources (Kominami et al ., 1992;Katagiri et al ., 1995;Lee-Robichaud et al ., 1995;Auchus et al ., 1998). In all cases, optimal molar ratios of b 5 to CYP17 increase the rate of the 17,20-lyase reaction over 10-fold, such that this rate approaches that of the 17 α -hydroxylase reaction.…”

Section: Control Of Adrenal 1720-lyase Activity At Adrenarchementioning

confidence: 99%

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Adrenarche – physiology, biochemistry and human disease

Auchus¹,

Rainey

2003

Clinical Endocrinology

259

148

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SummaryAdrenarche refers to the onset of dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) production from the adrenal zona reticularis that can be detected at around 6 years of age. The phenotypic result of adrenarche is pubarche or the development of axillary and pubic hair that occurs in both girls and boys at about age 8. The phenomenon of adrenarche is unique to human beings and to some Old World primates, and a reversal of adrenarche appears to occur in the ageing process. Premature and exaggerated adrenarche can be indicative of future onset of adult diseases, thus increasing the clinical relevance of adrenarche. The physiological triggers of adrenarche and the role(s) of DHEA-S remain speculative. However, the biochemical pathways that define adrenarche have been characterized in detail, and the appearance of key enzymes and cofactors in the adrenal zona reticularis track with the progression of adrenarche. This article reviews the clinical manifestations of adrenarche, the biochemistry of the enzymes involved in DHEA-S production, and the cell biology of the adrenal zona reticularis.Glucocorticoids and mineralocorticoids secreted by the adrenal glands are essential for the maintenance of vascular tone and carbohydrate metabolism or of blood volume and sodium balance, respectively. The testes and ovaries, by contrast, generate the sex steroids that are required for gametogenesis, secondary sexual characteristics and reproduction. However, the adrenal glands of adult human beings secrete generous quantities of the C 19 steroids dehydroepiandrosterone (DHEA) and DHEA-sulphate

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Section: Cyp11a (Cytochrome P450scc; Side-chain Cleavage Enzyme)mentioning

confidence: 99%

Section: Control Of Adrenal 1720-lyase Activity At Adrenarchementioning

confidence: 99%

Adrenarche – physiology, biochemistry and human disease

Auchus¹,

Rainey

2003

Clinical Endocrinology

259

148

View full text Add to dashboard Cite

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“…Whether this is true in P450 17A1 from other animals is unknown, and the zebrafish stimulation by b 5 (Fig. 3) is less than with human P450 17A1 (12,13).…”

Section: Discussionmentioning

confidence: 95%

“…1), has been proposed to involve a different form of reactive oxygen than that normally used in P450 reactions (FeO 3ϩ ), namely a ferric peroxide (Fe (II) O 2 Ϫ ) (9 -11). Only the second step (lyase reaction) is stimulated by cytochrome b 5 (b 5 ), at least in mammalian systems, and the first step (17␣-hydroxylation) is not (12,13). Phosphorylation has been reported to have the same effect (14 -16).…”

mentioning

confidence: 99%

Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2

Pallan

Nagy

Lei

et al. 2015

Journal of Biological Chemistry

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Background: Fish (and human) P450 17A1 catalyze both steroid 17␣-hydroxylation and 17␣,20-lyase reactions. A second fish P450, 17A2 (51% identical), catalyzes only 17␣-hydroxylation. Results: Crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1 are very similar. Conclusion: In kinetic analysis, the two-step oxidation of progesterone is more distributive than for pregnenolone. Significance: Small structural differences are associated with activities of the two fish P450s.

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“…Assay of Progesterone 17a a-Hydroxylase Activity Progesterone 17a-hydroxylase activity was determined by the methods described previously 13,16) with minor modification. Briefly, the membrane fraction containing CYP17 30 pmol and fp 2 90 pmol were preincubated at 37°C for 3 min, and the mixture was brought to 450 ml by addition of phosphate buffer 100 mM (pH 7.4), magnesium acetate 10 mM, and progesterone 1-50 mM.…”

Section: Expression Of Human Cyps and The Preparation Of Microsomes Amentioning

confidence: 99%

Metabolism and Interaction of Bisphenol A in Human Hepatic Cytochrome P450 and Steroidogenic CYP17.

Niwa

Fujimoto

Kishimoto

et al. 2001

Biological & Pharmaceutical Bulletin

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Bisphenol A (4,4Ј-isopropylidenediphenol, BPA) is widely used in the chemical industry in the manufacturing of epoxy, polycarbonate, and polyester-styrene resins, and trace levels of BPA leach from polycarbonate plasticware and resins used for food packaging materials. This compound is suspected to be an endocrine disrupter. 2) Additionally, it has been reported that exposure of male rats and mice to BPA may be associated with increased incidence of cancers of the hematopoietic system and that high doses of BPA cause reproductive toxicity and affect cellular development in these species. 3,4) However, the effect of BPA in vivo and its mechanism of action are still unclear.Cytochrome P450 (CYP) comprises a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs, carcinogens, and steroids including sex hormones. [5][6][7] In the rat, BPA is metabolized to DNA-reactive bisphenol-o-quinone through 5-hydroxybisphenol and bisphenol semiquinone, 4) and the formation of the DNA adducts in a microsomal activation system is markedly decreased by CYP inhibitors, 8) suggesting that CYPs are closely associated with the metabolism and toxicity of BPA in rats. However, there are few reports on BPA metabolism in humans and on the human CYP(s) that metabolizes BPA.Recently, we reported that BPA inhibits human hepatic CYP-mediated drug-metabolizing activities including aminopyrine N-demethylation, especially by CYP2C8 and CYP2C19. 9) Additionally, Hanioka et al. reported that the administration of BPA to male rats decreased the catalytic activities and protein levels of male-specific CYP isoforms (such as CYP2C11 and CYP3A2) in rat liver microsomes, 10) and that BPA inhibited the drug-metabolizing activities of rat hepatic CYP1A2, CYP2A2, CYP2B2, CYP2C11, CYP2D1, CYP2E1, and CYP3A2. 11) CYP17 is found in the endoplasmic reticulum of the adrenal cortex and gonads, and mediates both 17a-hydroxylase and 17,20-lyase reactions of pregnenolone and progesterone, and is thus involved in the biosynthesis of glucocorticoids and sex hormones. 12) Therefore endocrine disrupters (sex hormone-like compounds) may affect the activity of CYP17. Recently, we reported that the aminopyrine Ndemethylase activity of CYP17 was comparable with that of CYP3A4, a dominant CYP in human liver. 13) This paper describes an in vitro investigation of BPA metabolism by human hepatic CYPs and steroidogenic CYP17 based on the disappearance rate of parent compounds from an incubation mixture and the inhibitory effect of BPA on the progesterone 17a-hydroxylase activity of CYP17. MATERIALS AND METHODS MaterialsBisphenol A was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Progesterone, 17a-hydroxyprogesterone, and estrone were from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Human NADPH-cytochrome P450 reductase (fp 2 ) and hydrocortisone acetate were obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other reagents were of the highest purity commercially available. Expression o...

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The Role of Cytochrome b5 in the Biosynthesis of Androgens by Human P450c17

Cited by 223 publications

References 0 publications

Adrenarche – physiology, biochemistry and human disease

Adrenarche – physiology, biochemistry and human disease

Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2

Metabolism and Interaction of Bisphenol A in Human Hepatic Cytochrome P450 and Steroidogenic CYP17.

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