Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones

Niwa, Toshiyuki; Yabusaki, Yoshiyasu; Honma, Keiko; Matsuo, Nobutake; Tatsuta, K; Ishibashi, Fumihide; Katagiri, Masatoshi

doi:10.1080/004982598239290

Cited by 84 publications

(44 citation statements)

References 17 publications

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“…Hydroxylations Catalyzed by P450 17A1-The 16␣-hydroxylation of DHEA has previously been reported to be catalyzed by P450 3A4 (68,69). Upon monitoring the production of DHEA from 17␣-hydroxypregnenolone by P450 17A1 over time (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Yoshimoto

Gonzalez

Auchus

et al. 2016

Journal of Biological Chemistry

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We propose three mechanisms that can involve the FeO 3؉ entity and that explain the 18 O label in the acetic acid, two involving the intermediacy of an acetyl radical and one a steroid 17,20-dioxetane. P450 17A1 was found to perform 16-hydroxylation reactions on its 17␣-hydroxylated products to yield 16,17␣-dihydroxypregnenolone and progesterone, suggesting the presence of an active perferryloxo active species of P450 17A1 when its lyase substrate is bound. The 6␤-hydroxylation of 16␣,17␣-dihydroxyprogesterone and the oxidation of both 16␣,17␣-dihydroxyprogesterone and 16␣,17␣-dihydroxypregnenolone to 16-hydroxy lyase products were also observed. We provide evidence for the contribution of a compound I mechanism, although contribution of a ferric peroxide pathway in the 17␣,20-lyase reaction cannot be excluded. Cytochrome P450 (P450)3 enzymes catalyze oxidations of more chemicals than any other group of proteins (1). The list of reactions includes aliphatic and aromatic hydroxylations, heteroatom oxidations, epoxidations, and reactions involving both ring formation and cleavage (2-4). Many P450 reactions are important in the biosynthesis and degradation of steroids and sterols (4, 5), including several critical C-C bond cleavage reactions, i.e. those catalyzed by P450s 11A1, 17A1 (Fig. 1), 19A1, and 51A1 (6, 7).The mechanisms of the C-C cleavage reactions have been the subject of considerable interest and debate. One of the questions with P450s 17A1, 19A1, and 51A1 has been whether the active oxidant is a ferric peroxide (FeO 2 Ϫ ), which is an early intermediate following oxygen addition to the iron (Fig. 2, step 4) or the FeO 3ϩ species (Fig. 2, step 6), often referred to as compound I (4, 10, 11). With P450s 17A1 and 19A1, a variety of approaches has been applied, including theoretical calculations, biomimetic models, spectroscopy, substrate atom labeling, and kinetics (12-32).These C-C bond cleavage reactions are complex, and many of the results are ambiguous; also, a "mixed" mechanism would not be discerned in many of these experiments. One powerful approach originally used by Akhtar and co-workers (27-31) analyzes the actual reaction and can provide discrimination between the nucleophilic FeO 2 Ϫ and electrophilic FeO 3ϩ reactions (Fig. 2), based on the incorporation of 18 O label from O 2 into the carboxylic acid products (Fig. 3) (7). However, these experiments are complicated due to the ubiquitous presence of formic acid (P450 19A1 and 51A1 reactions) and acetic acid (P450 17A1) in laboratory settings. Thus, the data from such experiments are interpreted with the most confidence when the steroid substrates are labeled with 2 H or 13 C isotopes to facilitate analysis (15,33). Even then, the mass spectrometry results can be problematic, particularly if a shift of only one atomic mass unit is introduced and isotopologues derived from 18 O incorporation are not discriminated from molecules containing natural abundance 13 C atoms (33). The incorporation of one atom of 18 O label from O 2 into formic acid (F...

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Section: Discussionmentioning

confidence: 99%

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Yoshimoto

Gonzalez

Auchus

et al. 2016

Journal of Biological Chemistry

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“…As the clearance values for these two substances nevertheless are about the same, other metabolic pathways (or active renal excretion pathways) would be expected to contribute to the elimination of isoallopregnanolone to a higher degree than for allopregnanolone. Such a metabolic pathway might be degradation via cytochrome P-450 3A4 (CYP3A4), which is known to be involved in the metabolism of many sex hormones (Yamazaki and Shimada 1997;Niwa et al 1998;Tsuchiya et al 2005). …”

Section: Discussionmentioning

confidence: 99%

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

et al. 2008

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Rationale: The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known.Objectives: Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well known neurosteriod, acting via the GABA A receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA A receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA A receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.Methods: Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self rated sedation and mood rating scales were used during the test day.A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.Results: Exogenously administered isoallopregnanolone produced a dose dependent increase in the serum concentration of isoallopregnanolone. In parallel there was also a rise in the allopregnanolone concentration. There was a decrease in saccade eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.Conclusions: After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.3

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“…CYP3A4 is expressed in the prostate, breast, stomach, colon and small intestine and liver (Huang et al, 1996;Lown et al, 1997;Guengerich, 1999). CYP3A4 plays an important role in the testosterone (2β, 6β, o 15β-hydroxytestosterone) and estrogen (4-y 16α-hydroxylation) oxidation (Shou et al, 1997;Niwa et al, 1998). In recent years have been described several genetic polymorphisms that affect the expression of this gene (Chu and Fyles, 2007).…”

Section: Introductionmentioning

confidence: 99%

CYP3A4 Expression in Breast Cancer and its Association with Risk Factors in Mexican Women

Floriano-Sánchez¹,

Cárdenas-Rodríguez²,

Bandala³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones

Cited by 84 publications

References 17 publications

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

CYP3A4 Expression in Breast Cancer and its Association with Risk Factors in Mexican Women

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