Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vinca alkaloids are important chemotherapeutic agents, and their pharmacokinetic properties display significant interindividual variations, possibly due to CYP3A4-mediated metabolism. We have evaluated the relevance of this metabolism for the chemotherapeutic and the toxicological properties of these drugs. Analysis was performed using Chinese hamster ovary cell lines that expressed either CYP2D6 or CYP3A4. The latter cells metabolized vinblastine with a turnover number of 0.4 min(-1), resulting in a decreased cytotoxicity of this compound. Whereas vincristine and vinblastine at a concentration of 100 nM killed more than 90% of the parental cells, more than 50 and 35%, respectively, of cells that coexpressed CYP3A4 and cytochrome P450 (P450) reductase survived these treatments. No additional increase in cytotoxicity was noted above 100 nM. Similarly, preincubation of vinblastine with bacterial membranes that contained recombinant CYP3A4 and P450 reductase decreased the cytotoxicity of vinblastine for parental Chinese hamster ovary cells. We also demonstrate that the presence of vinblastine in a coculture of cells that expressed beta-galactosidase together with cells that expressed CYP3A4 strongly selected for the latter cells, resulting in an increased level of CYP3A4 in the surviving cell population. Similarly, treatment of the human colon adenocarcinoma cell line LS174T with vinblastine selected for a cell population with higher levels of endogenous CYP3A4 as revealed by immunohistochemistry without simultaneous increase of multidrug resistance protein 1 (MDR1). This is the first evidence that tumor P450s have the potential to contribute to the development of drug resistance during chemotherapy.
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PMID:Detoxication of vinca alkaloids by human P450 CYP3A4-mediated metabolism: implications for the development of drug resistance. 1087 37

CYP3A4, the predominant but variably expressed cytochrome P450 of adult human liver, is subject to multifaceted constitutive regulation as well as transcriptional induction by a variety of structurally unrelated xenobiotics. Using transient transfections in HepG2 cells, we previously demonstrated the existence of a potent xenobiotic-responsive enhancer module located between - 7.2 and - 7.8 kilobases upstream of the CYP3A4 transcription start site. Induction is mediated by interaction of transcription factor binding sites in the XREM with the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). To determine the in vivo relevance of these findings and to establish a mouse model of human CYP3A4 regulation, we have generated transgenic mice carrying constructs comprising the upstream regulatory region of the human CYP3A4 gene linked to the lacZ reporter gene. Constitutive expression was observed in a developmental, tissue- and cell-specific fashion that mirrors the human situation. In addition, robust hepatic and intestinal induction with a range of reagents known to activate PXR and/or CAR (e.g., dexamethasone, pregnenolone 16alpha-carbonitrile, and phenobarbital) was observed. However, no expression or induction was apparent with a construct lacking upstream sequences beyond - 3.2 kilobases. Histochemical staining for beta-galactosidase activity revealed that dose-dependent increases in transgene levels were associated with a zonal expansion of lacZ expressing hepatocytes, suggesting that xenobiotic induction of CYP3A genes operates primarily through the recruitment of more cells committed to expression. In summary, CYP3A4/lacZ transgenic mice provide an in vivo model for the study of the molecular mechanisms involved in the regulation of a significant human drug metabolizing enzyme.
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PMID:Transgenic mouse models of human CYP3A4 gene regulation. 1281 59