Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor

Harmsen, Stefan; Meijerman, Irma; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1007/s00280-008-0842-3

Cited by 85 publications

(65 citation statements)

References 22 publications

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“…Second, the time-dependent inhibition of CYP3A was actually substrate independent ( Figure 3). In the cell-based CYP3A activity assessment method by Harmsen et al, the cells were cultured in medium containing erlotinib for two consecutive days before measurement of the formation of 1'-hydroxymidazolam [16] . During the 2-d culture period, time dependent inhibition of CYP3A could occur, thus decreasing the formation of 1'-hydroxy midazolam.…”

Section: Discussionmentioning

confidence: 99%

“…Li et al found that erlotinib stimulated CYP3A-mediated midazolam metabolism in liver and intestinal microsomes [15] . Nevertheless, in a cell-based CYP3A activity assay, erlotinib was shown to decrease the formation of 1'-hydroxymidazolam, showing the potency to inhibit CYP3A activity [16] . As for the phase II enzymes, erlotinib was shown to exhibit inhibition activity on human UDP-glucuronosyltransferase (UGT) 1A1 [17] .…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…Given that DB was mainly metabolized by CYP3A4 in humans, higher expression of 3A, including 3A1 and 3A2, in male than in female mice and rats (Kato and Yamazoe, 1992) could enhance more metabolized DB, resulting in higher hepatotoxicity in male mice and lower oral bioavailability in male rats than in females. Concerning drug interaction, it should be noted that D. bulbifera may cause fatal toxicity when used with inducers of CYP3A4 such as rifampicin and hyperforin that also induce CYP2C9 expression (Chen et al, 2004;Harmsen et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Diosbulbin B In Vitro and In Vivo in Rats: Formation of Reactive Metabolites and Human Enzymes Involved

et al. 2014

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Diosbulbin B (DB), a major constituent of the furano-norditerpenes in Dioscorea bulbifera Linn, exhibits potential antineoplasmic activity and hepatotoxicity. The metabolism and reactive metabolites of DB in vitro (with human and animal liver microsomes) and in vivo in rats were investigated. The human enzymes involved in DB metabolism were identified. DB was first catalyzed into reactive metabolites of 2-butene-1,4-dial derivatives dependent on NADPH and then trapped by Tris base or oxidized to hemiacetal lactones (M12 and M13) in microsomal incubations. Tris base was used as buffer constituent and as a trapping agent for aldehyde. Methoxylamine and glutathione (GSH) were also used as trapping agents. DB metabolism in vivo in rats after oral administration was consistent with that in vitro. The structures of M12 and M13, as well as mono-GSH conjugates of DB (M31), were confirmed by nuclear magnetic resonance spectroscopy of the chemically synthesized products. The bioactivation enzymes of DB were identified as CYP3A4/5, 2C9, and 2C19. CYP3A4 was found to be the primary enzyme using human recombinant cytochrome P450 enzymes, specific inhibitory studies, and a relative activity factor approach for pooled human liver microsomes. Michaelis-Menten constants K m and V max were determined by the formation of M31. The reactive metabolites may be related to the hepatotoxicity of DB. The gender difference in CYP3A expression in mice and rats contributed to the gender-related liver injury and pharmacokinetics in mice and rats, respectively.

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“…However, this treatment is not always successful and often unwanted pharmacological effects occur in cancer patients, such as unresponsiveness or toxicity. A common cause for these unpredictable effects is up and down regulation of drug transporters or drug-metabolizing enzymes such as cytochrome P450 (Harmsen et al, 2009;Chen et al, 2010). Of these enzymes, CYP3A4 is quantitatively the most important because it metabolizes more than 50% of all drugs and the majority of the currently prescribed anticancer drugs (Anzenbacher and Anzenbacherová, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Cancer patients are often treated with multiple anticancer drugs or hormonal agents in combination with supplemental therapies to treat or prevent side effects (Harmsen et al, 2009). However, this treatment is not always successful and often unwanted pharmacological effects occur in cancer patients, such as unresponsiveness or toxicity.…”

Section: Introductionmentioning

confidence: 99%

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

et al. 2013

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Because cancer is often treated with combination therapy, unexpected pharmacological effects can occur because of drug-drug interactions. Several drugs are able to cause upregulation or downregulation of drug transporters or cytochrome P450 enzymes, particularly CYP3A4. Induction of CYP3A4 may result in decreased plasma levels and therapeutic efficacy of anticancer drugs. Since the pregnane X receptor (PXR) is one of the major transcriptional regulators of CYP3A4, PXR antagonists can possibly prevent CYP3A4 induction. Currently, a limited number of PXR antagonists are available. Some of these antagonists, such as sulphoraphane and coumestrol, belong to the so-called complementary and alternative medicines (CAM). Therefore, the aim was to determine the potential of selected CAM (b-carotene, Echinacea purpurea, garlic, Ginkgo biloba, ginseng, grape seed, green tea, milk thistle, saw palmetto, valerian, St. John's Wort, and vitamins B 6 , B 12 , and C) to inhibit PXR-mediated CYP3A4 induction at the transcriptional level, using a reporter gene assay and a real-time polymerase chain reaction assay in LS180 colon adenocarcinoma cells. Furthermore, computational molecular docking and a LanthaScreen time-resolved fluorescence resonance energy transfer (TR-FRET) PXR competitive binding assay were performed to explore whether the inhibiting CAM components interact with PXR. The results demonstrated that milk thistle is a strong inhibitor of PXR-mediated CYP3A4 induction. The components of milk thistle responsible for this effect were identified as silybin and isosilybin. Furthermore, computational molecular docking revealed a strong interaction between both silybin and isosilybin and PXR, which was confirmed in the TR-FRET PXR assay. In conclusion, silybin and isosilybin might be suitable candidates to design potent PXR antagonists to prevent drug-drug interactions via CYP3A4 in cancer patients.

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Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor

Cited by 85 publications

References 22 publications

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

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

Metabolism of Diosbulbin B In Vitro and In Vivo in Rats: Formation of Reactive Metabolites and Human Enzymes Involved

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

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