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

Zhang, Y.-Y.; Liu, Yan; Zhang, J.-W.; Ge, Guangbo; Liu, H.-X.; Wang, L.-M.; Sun, Jie; Yang, Ling

doi:10.3109/00498250903271989

Cited by 18 publications

(9 citation statements)

References 34 publications

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“…Furthermore, the IC 50 values for the inhibition of androsterone on HLM and UGT2B7, representing the inhibitor concentrations that inhibit 50% of the control activity, were determined by nonlinear curve fitting as described previously. 24 DES Glucuronidation in Individual HLM and Correlation Analysis. To reveal potential interindividual differences of hepatic DES glucuronidation, DES (5 μM) was incubated with individual HLM from 11 different donors, respectively.…”

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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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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“…Coumarin, diclofenac, dextromethorphan and ketoconazole were from ICN Biomedicals (Aurora, OH, USA). Human liver microsomes (HLMs) were prepared according to the method described by Guengerich (1989) and other previous reports [18,19] . Protein concentrations were determined using bovine serum albumin as a standard [20] .…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

et al. 2011

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Aim: To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo. Methods: The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.Results: The activity of CYP2C8 was inhibited with an IC 50 value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1′-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substratedependent: the IC 50 values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K I and k inact were 6.3 μmol/L and 0.035 min -1 for midazolam; 9.0 μmol/L and 0.045 min -1 for testosterone; and 10.1 μmol/L and 0.058 min -1 for nifedipine. Conclusion: The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrateindependent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.

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“…The optimal conditions for microsomal incubation were described previously [ 12 ]. The incubation mixture, with a total volume of 200 μ L, consisted of 100 mM potassium phosphate buffer (pH 7.4), an NADPH-generating system (10 mM glucose 6-phosphate, 1 unit/mL of glucose 6-phosphate dehydrogenase, and 4 mM MgCl 2 ), liver microsomes (0.3 mg/mL), or recombinant CYP450s (15 nM).…”

Section: Methodsmentioning

confidence: 99%

Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes

Shi

Zhang

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 μM and 2.22 μM for CYP1A2 and CYP3A4, respectively. The metabolism of xanthotoxol obeyed the typical monophasic Michaelis-Menten kinetics and V max, K m, and CLint values were calculated as 0.55 nmol·min−1·mg−1, 8.46 μM, and 0.06 mL·min−1·mg−1. In addition, the results of molecular docking showed that xanthotoxol was bound to CYP1A2 with hydrophobic and π-π bond and CYP3A4 with hydrogen and hydrophobic bond. We predicted the hepatic clearance (CLH) and the CLH value was 15.91 mL·min−1·kg−1 body weight. These data were significant for the application of xanthotoxol and xanthotoxol-containing herbs.

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

Cited by 18 publications

References 34 publications

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

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

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes

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