Evaluation of the toxicological relevance of CYP3A4 induction.
CYP3A4 is the most abundant cytochrome P450 in human liver, comprising approximately 30% of the total liver P450 content. This enzyme has an important role in endogenous processes, most notably steroid catabolism, and also plays a fundamental role in the metabolism of more than half of the clinically used drugs currently prescribed. The majority of CYP3A substrates are also capable of upregulating CYP3A activity, mainly through transcriptional activation. The molecular mechanisms that underlie the transcriptional activation of CYP3A4 are complex, with many steroid hormone nuclear receptors, including GR, PXR, VDR and CAR, playing a role in these mechanisms. However, the net result of transcriptional activation is an increase in the metabolism of the inducing compounds and, therefore, increased clearance. An important side effect of this transcriptional activation is that co-administered chemicals metabolized by CYP3A may also have their pharmacokinetics altered. Such changes can result in reduced clinical efficacy of drugs, resulting in poor patient response, or the development of an adverse drug response. This review will examine examples of established interactions caused through transcriptional activation of CYP3A4, and speculate on whether such effects are clinically important and should be considered during the design of treatment regimes or, alternatively, are relatively minor and cause little physiological effects.
Plant
Nick J
NJ
University of Surrey, Molecular Toxicology Group, School of Biomedical and Life Sciences, Guildford, Surrey, GU2 7XH, UK. N.Plant@surrey.ac.uk
Gibson
G Gordon
GG
D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics; D019295:Computational Biology; D015870:Gene Expression; D005819:Genetic Markers; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D051381:Rats; D012098:Reproduction / Q000187:drug effects
D005819:Genetic Markers