Cytochrome P450 3A and their regulation.
CYP3A isozymes collectively comprise the largest portion of the liver and small intestinal CYP protein and they are involved in the metabolism of 45-60% of all currently used drugs. In addition to drugs, CYP3A isozymes metabolise a variety of other compounds including steroid hormones, toxins and carcinogens. It is also well known that the hepatic expression and activity of CYP3A isozymes varies from individual to individual. The involvement of this variability in harmful interactions frequently encountered in development and application of drugs that are CYP3A substrates is well documented. It has also been postulated that variable CYP3A expression could affect an individual's predisposition to cancers caused by environmental carcinogens that are metabolised by CYP3A. The elucidation of factors controlling an individual's CYP3A activity could permit personalised dose adjustments in therapies with its substrates and may also possibly lead to the identification of sub-populations at increased risk for several common cancers. However, until recently, the development of markers predictive for the individual CYP3A expression has been slower than for other drug metabolising enzymes. Here we summarise the current status of our understanding of the genetics and regulation of the expression of CYP3A, including the recently described markers of the CYP3A5 and CYP3A7 polymorphisms. These latter markers are expected to speed up the development of activity probes for the individual CYP3A isozymes and to aid in our understanding of their individual functions.
Burk
Oliver
O
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.
Wojnowski
Leszek
L
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic; D015262:Xenobiotics / Q000493:pharmacokinetics
D015262:Xenobiotics; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating