Human fetal liver (HFL) cells express major drug metabolic enzymes CYP3A4, CYP3A5 and CYP3A7. In the fetal hepatocytes, betamethasone and dexamethasone (DEX) markedly enhanced the expression levels of CYP3A4 and CYP3A7 mRNAs and slightly increased the expression level of CYP3A5 mRNA. Interestingly, a high correlation between the CYP3A induction ability and the intensity of anti-inflammatory eff...

The widely prescribed lipid-lowering statins are considered to be relatively safe drugs. However, the risk of severe myopathy and drug interactions as a consequence of statin therapy provides a challenge for development of novel cholesterol-lowering agents, targeting enzymes other than HMG-CoA reductase. The novel pyridylethanol-(phenylethyl)amine derivative, (2-((3,4-dichlorophenethyl)(propyl)...

CYP3A4 is the most abundant cytochrome P450 (P450) in human liver, comprising approximately 30% of the total liver P450 content. This enzyme has an important role in steroid catabolism and metabolism of foreign compounds, with the majority of pharmaceutical compounds being substrates for CYP3A4. The molecular mechanisms that underlie transcriptional activation of CYP3A4 are complex with many st...

Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is...

Rosiglitazone and pioglitazone are thiazolidinediones used for treatment of noninsulin-dependent diabetes mellitus. These compounds, along with troglitazone, were evaluated for the ability to induce cytochrome P450 enzymes (P450) in primary human hepatocyte cultures and to inhibit P450 in human microsomes. In induction studies, all three thiazolidinediones caused a dose-dependent increase in CY...

Previously we described a transgenic mouse model [FVB/NTg(CYP3A4-luc)Xen] using a reporter construct consisting of 13 kilobases of the human CYP3A4 promoter driving the firefly luciferase gene in the inbred FVB/N mouse strain. Here we report regulation of the same CYP3A4-luc reporter gene in a transgenic outbred mouse strain (CD-1) and in a transgenic rat (Sprague-Dawley). Basal reporter expres...

Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D-regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell line...

Assessment of foreign chemical inducibility on CYP3A4 is necessary to optimize drug therapies. The properties of chemicals such as pesticides, however, are not well investigated. In the present study, properties of various pesticides on human CYP3A4 induction have been tested using HepG2-derived cells stably expressing the CYP3A4 promoter/enhancer (3-1-10 cells) and the human pregnane X recepto...

CYP3A4 (cytochrome P450 3A4) is involved in the metabolism of more than 50% of drugs and other xenobiotics. The expression of CYP3A4 is induced by many structurally dissimilar compounds. The PXR (pregnane X receptor) is recognized as a key regulator for the induction, and the PXR-directed transactivation of the CYP3A4 gene is achieved through a co-ordinated mechanism of the distal module with t...

Induction of cytochrome P450 (P450) activity in the clinic can result in therapeutic failure such as tissue rejection in transplant patients or unwanted pregnancy, among others. CYP3A4 is by far the most abundant isoform and is responsible for the majority of P450-related metabolism of all marketed drugs. However, it is of importance to understand the significance of induction mediated through ...