NADPH-Dependent Metabolism of Estrone by Human Liver Microsomes

Lee, Anthony J.; Mills, Laura H.; Kosh, J.W.; Conney, Allan H.; Zhu, Bao Ting

doi:10.1124/jpet.300.3.838

Cited by 34 publications

(28 citation statements)

References 44 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: 90%

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: 90%

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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“…Although 4-OH estrogens are formed in much smaller amounts than 2-OH estrogens in the liver (3,4), 4-OH estradiol may accumulate in target organs, such as the endometrium, when high levels of 2-OH estradiol inhibit the O-methylation of 4-OH estradiol (11,12). In CD-1 mice, 4-OH estradiol more strongly induces endometrial adenocarcinoma than does 2-OH estradiol (13).…”

Section: Introductionmentioning

confidence: 99%

“…1]. 2-Hydroxylation is the major oxidative pathway, catalyzed mainly by CYP1A2 in the liver (3,4) and by CYP1A1 in the endometrium (5) and other extrahepatic tissues. In Syrian hamsters, almost 100% of whom develop kidney tumors after exposure to estradiol, 2-hydroxylated estrogens (2-OH estrogens) do not induce tumors (6,7).…”

Section: Introductionmentioning

confidence: 99%

Genetic Factors in Catechol Estrogen Metabolism in Relation to the Risk of Endometrial Cancer

Doherty

Weiss

Freeman

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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2-Hydroxylated metabolites of estrogen have been shown to have antiangiogenic effects and inhibit tumor cell proliferation, whereas 4-hydroxylated metabolites have been implicated in carcinogenesis. We examined whether polymorphisms in certain genes involved in estrogen metabolism are associated with endometrial cancer risk in a populationbased case-control study with 371 cases and 420 controls. Based on previously published genotype-phenotype correlation studies, we defined variant alleles thought to increase estrogen 2-hydroxylation as presumptively low-risk (CYP1A1 m1 T6235C and m2 Ile 462 Val) and those thought to increase estrogen 4-hydroxylation as high-risk (CYP1A1 m4 Thr 461 Asn, CYP1A2 A734C, and CYP1B1 Leu 432 Val). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. Carrying at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer [ORs (95% CIs), 0.64 (0.44-0.93) and 0.54 (0.30-0.99), respectively]. No strong alteration in risk was observed among women with any of the putative high-risk alleles. When CYP1A1, CYP1A2, and CYP1B1 genotypes were combined and ranked by the number of putative low-risk genotypes carried, women with four or five low-risk genotypes had a reduced risk of endometrial cancer (OR, 0.29; 95% CI, 0.15-0.56) compared with women with one or none. No appreciable alteration in risk was observed among women carrying two or three low-risk genotypes. Some of our findings are consistent with the hypothesis that increased estrogen 2-hydroxylation is associated with decreased endometrial cancer risk, but replication of these results is required before any firm conclusions can be reached.

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“…During our recent analysis of the NADPH-dependent metabolism of [ 3 H]E 2 and [ 3 H]estrone to various hydroxylated or keto metabolites by human liver microsomes (Lee et al, 2001(Lee et al, , 2002, we consistently detected a cluster of coeluted radioactive peaks at the end of a 60-min HPLC run, with their chromatographic polarities less than estrone. Notably, similar nonpolar radioactive peaks were also noted earlier when radioactive E 2 or estrone was incubated with rat or mouse liver microsomes (Aoyama et al, 1990;Haaf et al, 1992;Suchar et al, 1995Suchar et al, , 1996Zhu et al, 1997Zhu et al, , 1998.…”

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confidence: 99%

NADPH-DEPENDENT FORMATION OF POLAR AND NONPOLAR ESTROGEN METABOLITES FOLLOWING INCUBATIONS OF 17β-Estradiol WITH HUMAN LIVER MICROSOMES

Lee

Zhu²

2004

Drug Metab Dispos

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ABSTRACT:By using a versatile high-pressure liquid chromatography method (total elution time ϳ135 min) developed in the present study, we detected the formation of some 20 nonpolar radioactive metabolite peaks (designated as M1 through M20), in addition to a large number of polar hydroxylated or keto metabolites, following incubations of [ 3 H]17␤-estradiol with human liver microsomes or cytochrome P450 3A4 in the presence of NADPH as a cofactor. The formation of most of the nonpolar estrogen metabolite peaks (except M9) was dependent on the presence of human liver microsomal proteins, and could be selectively inhibited by the presence of carbon monoxide. Among the four cofactors (NAD, NADH, NADP, NADPH) tested, NADPH was the optimum cofactor for the metabolic formation of polar and nonpolar estrogen metabolites in vitro, although NADH also had a weak ability to support the reactions. These observations suggest that the formation of most of the nonpolar estrogen metabolite peaks requires the presence of liver microsomal enzymes and NADPH. Chromatographic analyses showed that these nonpolar estrogen metabolites were not the monomethyl ethers of catechol estrogens or the fatty acid esters of 17␤-estradiol. Analyses using liquid chromatography/mass spectrometry and NMR showed that M15 and M16, two representative major nonpolar estrogen metabolites, are diaryl ether dimers of 17␤-estradiol. The data of our present study suggest a new metabolic pathway for the NADPH-dependent, microsomal enzyme-mediated formation of estrogen diaryl ether dimers, along with other nonpolar estrogen metabolites.The endogenous estrogens undergo extensive metabolism in humans (Martucci and Fishman, 1993;Zhu and Conney, 1998a), such as oxidation (largely mediated by P450 enzymes), interconversion between 17␤-estradiol and estrone, and various conjugation-deconjugation reactions. In addition, the catechol-O-methyltransferase-mediated O-methylation of endogenous catechol estrogens to monomethyl ethers (Zhu and Conney, 1998b) and the acyltransferase-mediated esterification of estrogens with fatty acyl-CoAs (Mellon-Nussbaum et al., 1982;Hochberg, 1998) result in the formation of lipophilic estrogen derivatives. These multiple metabolic pathways not only determine the pharmacokinetic features of the endogenous estrogens in the body and in various target tissues, but they also diversify the biological actions of endogenous estrogens in certain target sites through metabolic formation of biologically active estrogen metabolites, such as 4-hydroxyestradiol, 15␣-hydroxyestradiol, 16␣-hydroxyestrone, and 2-methoxyestradiol (a predominant O-methylation product of 2-hydroxyestradiol).During our recent analysis of the NADPH-dependent metabolism of Notably, similar nonpolar radioactive peaks were also noted earlier when radioactive E 2 or estrone was incubated with rat or mouse liver microsomes (Aoyama et al., 1990;Haaf et al., 1992;Suchar et al., 1995Suchar et al., , 1996Zhu et al., 1997Zhu et al., , 1998. Further characterization of these nonpolar met...

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NADPH-Dependent Metabolism of Estrone by Human Liver Microsomes

Cited by 34 publications

References 44 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

Genetic Factors in Catechol Estrogen Metabolism in Relation to the Risk of Endometrial Cancer

NADPH-DEPENDENT FORMATION OF POLAR AND NONPOLAR ESTROGEN METABOLITES FOLLOWING INCUBATIONS OF 17β-Estradiol WITH HUMAN LIVER MICROSOMES

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