Progesterone and Testosterone Hydroxylation by Cytochromes P450 2C19, 2C9, and 3A4 in Human Liver Microsomes

Yamazaki, Hiroshi; Shimada, Tsutomu

doi:10.1006/abbi.1997.0302

Cited by 279 publications

(213 citation statements)

References 38 publications

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“…The in vitro hydroxylation of naturally occurring steroids, including progesterone, has been reported by other investigators as follows: progesterone [15][16][17], testosterone [15,16,18], androstedione [16], estradiol [19], and esterone [20]. The hydroxylation of synthetic steroid derivatives has also been reported: medroxyprogesterone acetate [21], Org 4060 and Org 30659 [22].…”

Section: Discussionmentioning

confidence: 89%

Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons

Yan

Nanovskaya

Zharikova

et al. 2008

Biochemical Pharmacology

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Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogestrone caproate (17-HPC), used for treatment of preterm deliveries, during its perfusion across the dually perfused human placental lobule. Previously, we demonstrated that the drug is not hydrolyzed, neither in vivo nor in vitro, to progesterone and caproate. Therefore, the hypothesis for this investigation is that 17-HPC is actively metabolized by human and baboon (Papio cynocephalus) hepatic and placental microsomes. Baboon hepatic and placental microsomes were investigated to validate the nonhuman primate as an animal model for drug use during pregnancy. Data presented here indicate that human and baboon hepatic microsomes formed several mono-, di-, and tri-hydroxylated derivatives of 17-HPC. However, microsomes of human and baboon placentas metabolized 17-HPC to its mono-hydroxylated derivatives only in quantities that were a fraction of those formed by their respective livers, except for two metabolites (M16' and M17') that are unique for placenta and contributed to 25% and 75% of the total metabolites formed by human and baboon, respectively. The amounts of metabolites formed, relative to each other, by human and baboon microsomes were different suggesting that the affinity of 17-HPC to CYP enzymes and their activity could be species-dependent.

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Section: Discussionmentioning

confidence: 89%

Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons

Yan

Nanovskaya

Zharikova

et al. 2008

Biochemical Pharmacology

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“…Our results are consistent with reports that CYP2C19 can 21-hydroxylate progesterone but not 17-hydroxyprogesterone, thus possibly ameliorating the mineralocorticoid deficiency, but not the glucocorticoid deficiency. 8,9 Other modifier genes that were not accounted for in our study may contribute to the observed 21OHD genotype phenotype inconsistencies as it is possible that other enzymes contribute to extra-adrenal 21-hydroxylation. Besides CYP2C19, CYP3A4 was reported to 21-hydroxylate progesterone, but not 17-hydroxyprogesterone.…”

Section: Resultsmentioning

confidence: 93%

“…It has been shown that hepatic cytochrome P450 drug-metabolizing enzyme CYP2C19 can 21-hydroxylate progesterone but not 17-hydroxyprogesterone, possibly ameliorating mineralocorticoid deficiency, but not glucocorticoid deficiency. 8,9 A large interindividual variability in CYP2C19 activity that is mainly determined by genetic polymorphisms of this enzyme has been observed. CYP2C19*2 allele accounts for 93% of the alleles that code for a non-functional enzyme in the Caucasians and in the Slovene population.…”

Section: Introductionmentioning

confidence: 99%

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Grošelj¹,

Tanšek²,

Podkrajšek³

et al. 2016

ACSi

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Extraadrenal enzymes such as CYP2C19 may participate in residual 21-hydroxylation of progesterone leading to milder phenotypes of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). Among 94 21OHD patients from the Slovene national registry 28 were homozygous or compound heterozygous for severe CYP21A2 mutations. We have reviewed their clinical phenotype and obtained information on maintenance doses of hydrocortisone and fludrocortisone. All patients were genotyped for CYP2C19*2 and CYP2C19*17 alleles. Among eleven patients with CYP2C19*1/*17 genotype, all had salt-wasting 21OHD. Out of 17 patients with CYP2C19 genotypes leading to normal or decreased CYP2C19 activity, 15 had salt-wasting, one had simple virilizing and one had non-classical 21OHD. CYP2C19*1/*17 genotype was associated with lower maintenance dose of fludrocortisone (p = 0.04), but not of hydrocortisone (p > 0.05). Increased CYP2C19 activity could slightly ameliorate mineralocorticoid deficiency in 21OHD.

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“…In addition, the CAR activator phenytoin has been found to regulate androgen and testosterone metabolism through CYP3A in the mouse brain (Rosenbrock et al 1999;Meyer et al 2006). In the liver, CYP3A can also metabolize testosterone and progesterone (Yamazaki and Shimada 1997). It is clear from these collected findings that regulation of drug metabolizing enzymes such as UGTs and CYPs by activation of CAR and PXR can have an effect on endocrine signaling through the increased metabolism of hormones.…”

Section: Endocrine Homeostasismentioning

confidence: 97%

Nuclear receptors CAR and PXR in the regulation of hepatic metabolism

Tien

Negishi

2006

Xenobiotica

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Abstract1. The nuclear receptors CAR and PXR were first characterized as xenosensing transcription factors regulating the induction of phase I and II xenobiotic metabolizing enzymes as well as transporters in response to exogenous stimuli. 2.It has now become clear, however, that these receptors cross talk with endogenous stimuli as well which extends their regulation to various physiological processes such as energy metabolism and cell growth. As recognition of the function of these receptors has widened, the molecular mechanism of their regulation has evolved from simple protein-DNA binding to regulation by complex protein-protein interactions. 3.Novel mechanisms as to how xenobiotic exposure alters hepatic metabolic pathways such as gluconeogenesis and β-oxidation have emerged. At the same time, the molecular mechanism of how endogenous stimuli, such as insulin, regulate xenobiotc metabolism via CAR and PXR have also become evident.

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Progesterone and Testosterone Hydroxylation by Cytochromes P450 2C19, 2C9, and 3A4 in Human Liver Microsomes

Cited by 279 publications

References 38 publications

Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons

Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Nuclear receptors CAR and PXR in the regulation of hepatic metabolism

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