Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Liu, Yong; Zhao, Jiuyang; Wang, Liming; Ge, Guangbo; Gao, Yang; Li, Wei; Liu, Hongtao; Liu, Hui‐Xin; Zhang, Yanyan; Sun, Jie; Yang, Ling

doi:10.1124/dmd.108.022525

Cited by 26 publications

(16 citation statements)

References 34 publications

(37 reference statements)

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“…However, there are also correlations between M-1 formation and CYP1A2 (r = 0.65, p < 0.05), CYP2A6 (r = 0.67, p < 0.05), and CYP2C8 (r = 0.81, p < 0.01) marker reactions; between M-2 formation and CYP1A2 (r = 0.63, p < 0.05), CYP3A4 (r = 0.88, p < 0.001; r = 0.84, p < 0.01) marker reactions; and between M formation and CYP3A4 (r = 0.84, p < 0.01; r = 0.81, p < 0.01) marker reactions (Table 2). These correlations probably resulted from high correlations among individual CYP isoforms, as described previously (Zhang et al 2008b). For example, statistically significant correlations between CYP2C8 and CYP3A4 activities (for testosterone 6β-hydroxylation, r = 0.87, p < 0.001; for paclitaxel 3′-p-hydroxylation, r = 0.86, p < 0.001) were obtained in the panel of liver microsomes used (Zhang et al 2009b).…”

Section: Correlation Studymentioning

confidence: 97%

C-7 configuration as one of determinants in taxanes metabolism by human cytochrome P450 enzymes

Zhang¹,

Liu²,

Zhang³

et al. 2009

Xenobiotica

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Taxanes exhibit a high tendency to epimerize at C-7 under physiological conditions. This study aimed to investigate the composite effect of C-7 configuration and other substructural elements on the metabolic properties of taxanes. Cephalomannine, 7-epi-cephalomannine, 10-deacetyl-paclitaxel, and 7-epi-10-deacetyl-paclitaxel were chosen as model compounds. In human liver microsomes, 7-epi-cephalomannine was subject to C-13 lateral chain (M-1) and diterpenoid core monohydroxylation (M-2), mediated by cytochrome P450 (CYP) 3A4 and CYP2C8, respectively. However, only one 7-epi-10-deacetyl-paclitaxel metabolite (M), monohydroxylated at taxane ring by CYP2C8, was detected. In comparison with cephalomannine, the catalytic efficiency of CYP2C8 for 7-epi-cephalomannine was about five-fold higher due to the decreased K(m). Although CYP2C8 showed a high capacity for metabolizing 7-epi-10-deacetyl-paclitaxel, 10-deacetyl-paclitaxel was hardly metabolized under the identical incubation conditions. In conclusion, C-7 configuration represents one of the most important structural determinants in taxanes metabolism.

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Section: Correlation Studymentioning

confidence: 97%

C-7 configuration as one of determinants in taxanes metabolism by human cytochrome P450 enzymes

Zhang¹,

Liu²,

Zhang³

et al. 2009

Xenobiotica

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“…HLM was prepared according to the methods described by our previous study. 22 Sprague− Dawley rats (n = 10, male; weight, 180−220 g) were purchased from Dalian Medical University with the approval of the local Institutional Animal Care & Use Committee. The animals had free access to tap water and pellet diet.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine

Zhu

Liu

et al. 2012

Chem. Res. Toxicol.

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Diethylstilbestrol (DES), a synthetic estrogen, is famous for its carcinogenic effects. Human exposure to this compound can occur frequently through dietary ingestion and medical treatment. Glucuronidation has been demonstrated to be a predominant metabolic pathway for DES in human. Therefore, glucuronidation metabolism may have a significant impact on its toxicities, and it is essential to clarify this metabolic pathway. Accordingly, this in vitro study is designed to characterize the UGTs involved in DES glucuronidation and, furthermore, to identify the roles of individual isoforms in the reaction in liver and intestine. Human liver microsomes (HLM) displayed much higher potential for DES glucuronidation than human intestinal microsomes (HIM). The intrinsic clearances in HLM and HIM were demonstrated to be 459 and 14 μL/min/mg protein, respectively. Assays with recombinant UGTs demonstrated that UGT1A1, -1A3, -1A8, and -2B7 could catalyze DES glucuronidation, among which UGT2B7 showed the highest affinity. Chemical inhibitors of UGT2B7 and UGT1A1/1A3 both displayed similar inhibition against the reaction in UGT2B7 and HLM. In addition, DES glucuronidation in individual HLM exhibited a large individual variability and strongly correlated to UGT2B7 activity. All evidence indicates that UGT2B7 may act as a major enzyme responsible for DES glucuronidation in human liver. For HIM, both UGT2B7 inhibitor and UGT1A1/1A3/1A8 inhibitor exerted moderate inhibition. It is suggested that although UGT2B7 contributes to DES glucuronidation in intestine, other UGTs may contribute equally. In summary, this study characterizes human UGTs involved in DES glucuronidation in human liver and intestine, which may be helpful for further study about DES-related toxicities. Figure 1), a synthetic nonsteroid estrogen, is famous for its carcinogenicity. Human exposure to this compound can occur directly or indirectly through dietary ingestion and medical treatment. 1−4 DES was once prescribed widely to millions of pregnant women in false hopes of preventing miscarriage and other pregnancy complications in the United States. 1 It is now still accepted as an efficient therapy for the treatment of prostate and breast cancers. 2,3 Aside from its wide clinical applications, DES has found widespread application as a growth promoter in feeding cattle, sheep, and poultry. 4 It was estimated that in 1971 alone as much as 27600 kg of DES was used in livestock feeding in the United States. 5 After widespread and extensive exposures to DES, numerous serious health problems have been encountered. DES was established to cause the rare clear cell adenocarcinoma (CCAC) of the vagina and cervix in "DES daughters" (who are exposed to DES before birth). 6 In addition to CCAC, these daughters were found to suffer from malformations of their genital tracts, which can result in severe pregnancy and fertility problems. 7−9 Just like DES daughters, DES sons were also found to be prone to DES damage in the genitalia. 10 In company with daughters and so...

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“…The 6-methyl and 17-acetoxy groups on the MPA molecule make it more resistant to hepatic metabolism than progesterone. Based on in vitro studies, three main hydroxylation sites of MPA were proposed to be 6␤, 2␤ and 1␤ positions, generated by CYP3A [5]. One would also expect the double bond and ketone group in ring A to undergo reduction, forming dihydro and tetrahydro metabolites of MPA.…”

Section: Metabolism and Pharmacokinetics Of Mpamentioning

confidence: 98%

Reprint of “Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: Is it safe?”

Stanczyk

Bhavnani

2015

The Journal of Steroid Biochemistry and Molecular Biology

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Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Cited by 26 publications

References 34 publications

C-7 configuration as one of determinants in taxanes metabolism by human cytochrome P450 enzymes

C-7 configuration as one of determinants in taxanes metabolism by human cytochrome P450 enzymes

Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine

Reprint of “Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: Is it safe?”

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