CYPs cytochrome genetic polymorphisms

It has now been established that genetic polymorphisms in drug metabolizing enzymes such as the cytochrome P450s (CYP) and the phase II enzyme, thiopu-rine methyltransferase, are responsible for inter-individual variability in response and adverse reactions [12, 13]. However, at the present time, the impact of poly-... 

Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, Brockmoller J. Effect of genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs clinical relevance. Clin Pharmacokinet 2005 44(12) 1209-25. 

Drugs that are metabolized by the cytochrome P-450 (CYP) isoenzymes CYP2D6, CYP2C9, and CYP2C19 also exhibit genetic polymorphisms. An example of CYP2D6 metabolism is debrisoquine. In about 5-10 /o of Caucasians in North America and Europe and about 1% of Asians, 4-hydroxylation of debrisoquine is reduced, and such individuals are at increased risk for toxicity (orthostatic hypotension). Beta blockers (metoprolol and timolol), antiarrhythmic drugs (encainide and flecainide), tricyclic antidepressants... 

Figure 43-1 I Schematic view of the role of NAT enzymes in the metabolism of aromatic amines. N-acetylation might be a detoxification reaction in a number of cases however, after N-hydroxylation of aromatic amines (e.g., by CYP enzymes), NAT enzymes can bioactivate these intermediates by either 0-acetylation or intramolecular N,0-acety transfer, leading to the formation of nitrenium ions, which might react with DNA or alternatively be detoxified by, for example, GST enzymes. Importantly, it is shown that a number of other biotransformation enzymes are also involved in the metabolism of aromatic amines as well. (Redrawn from Wormhoudt LW, Commandeur jNM, Vermeuien NPE. Genetic polymorphisms of human N-acetyitransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999 29 59-124. Reproduced by permission from Taylor and Francis, Inc.)...

Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (CYP) enzymes being inhibited by concomitant administration of other drugs. Additionally, genetic polymorphisms of important CYP... 

Imai J, leiri I, Mamiya K, Miyahara S, Furuumi H, Nanba E et al. Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients Genetic analysis of the CYP2C9 locus. Pharmacogenetics 10(1), 85-89,2000. 

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