CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that t...

Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity rema...

Ritonavir is a human immunodeficiency virus (HIV) protease inhibitor and an inhibitor of cytochrome P450 3A4, the major human hepatic drug-metabolizing enzyme. Given the potent inhibition of CYP3A4 by ritonavir, subtherapeutic doses of ritonavir are used to increase plasma concentrations of other HIV drugs oxidized by CYP3A4, thereby extending their clinical efficacy. However, the mechanism of ...

Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP...

Modulation of UDP-glucuronosyltransferase 2B7 (UGT2B7)-catalyzed morphine glucuronidation by cytochrome P450 (P450) was studied. The effects of P450 isozymes on the kinetic parameters of UGT2B7-catalyzed glucuronidation of the morphine 3-hydroxyl group were examined by simultaneous expression of UGT2B7 and either CYP3A4, -1A2, or -2C9 in COS-1 cells. Although coexpression of CYP3A4 with UGT2B7 ...

Mibefradil (Posicor) was developed as a calcium channel blocker for the treatment of chronic hypertension. The compound was withdrawn from the market in 1998 because of the potential for rhabdomyolysis, renal failure, or bradycardia when it was coadministered with other drugs. Mibefradil has previously been shown to be a potent reversible (IC(50) = 0.3-2 μM) and mechanism-based (K(i) = 2.3 μM; ...

Ritonavir is a human immunodeficiency virus (HIV) protease inhibitor and an inhibitor of cytochrome P450 3A4, the major human hepatic drug-metabolizing enzyme. Given the potent inhibition of CYP3A4 by ritonavir, subtherapeutic doses of ritonavir are used to increase plasma concentrations of other HIV drugs oxidized by CYP3A4, thereby extending their clinical efficacy. However, the mechanism of ...

The monotopic, endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) undergo variable proteolytic turnover. CYP3A4, the dominant human liver drug-metabolizing enzyme, is degraded via a ubiquitin (Ub)-dependent 26S proteasomal pathway after heterologous expression in Saccharomyces cerevisiae. This turnover involves the Ub-conjugating enzyme Ubc7p and the 19S proteasomal subunit Hrd2p but ...

CYP3A4, the predominant cytochrome P450 expressed in human liver, is responsible for the metabolism of endogenous steroids and many drugs. On the basis of pharmacokinetic studies in patients with hormonal derangements and the effects of replacement therapy, it has been suggested that iodothyronines decrease CYP3A4-mediated drug metabolism, whereas glucocorticoids and GH enhance CYP3A4 activity....

CYP3A4 metabolizes many drugs on the market. Although transcriptional regulation of CYP3A4 is known to be tightly controlled by some nuclear receptors (NR) including vitamin D receptor (VDR/NR1I1), posttranscriptional regulation of CYP3A4 remains elusive. In this study, we show that noncoding microRNAs (miRNAs) may control posttranscriptional and transcriptional regulation of CYP3A4 by directly...