C O N T E N T S
See AlsoDescriptionGenetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With the acetylator polymorphism and N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly 50:50 in the population of Canada. This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. Harris et al. (1) and Evans et al. (2) showed that in certain individuals the antituberculosis drug isoniazid disappeared more quickly from the blood than in others. The rate of disappearance with the earlier tests appeared bimodal, with the types genetically determined and fast metabolism expressing itself as the dominant condition. More sophisticated tests enable the heterozygotes to be distinguished almost, if not quite, completely from both the homozygous types. The metabolism in question is the acetylation of the drug, and the same system controls the acetylation of a number of other substances including the drug dapsone used for the treatment of leprosy. The system is thus of some importance in clinical medicine. The frequency of rapid acetylators varies over a wide range, being especially high in Mongoloid peoples. AbstractsDiscussionIn the 1940s doctors noticed that some people developed serious side effects from an antituberculosis drug. Much later, doctors realized that these people had a mutation in a gene called N-acetyltransferase (NAT), which adds a small molecule to drugs as they pass through the liver or intestine. This small molecule helps some drugs become effective, detoxifies some cancer-causing substances – such as those found in tobacco smoke – or causes substances found in some cooked meats to become more carcinogenic. It turns out that there are four different forms of NAT. One form – called the fast form – causes people to process drugs very efficiently, and therefore to respond well to those drugs. The three other forms of the gene cause a person to process drugs very slowly. People who have one of these three forms of the gene, referred to as slow acetylators, respond poorly to some drugs and tend to show more side effects because the unprocessed chemical remains at high levels in the blood. It was these slow acetylators who had responded poorly to the antituberculosis drug. Because N-acetyltransferase is also involved in processing cancer-causing chemicals, fast and slow acetylators have different risk levels for some cancers. Fast acetylators are at high risk for colon cancer, while slow acetylators are at increased risk for bladder cancer. Post-menopausal women who are slow acetylators are also more likely to develop breast cancer as a result of smoking, according to one study. All three slow forms of NAT are autosomal recessive. That is, a person has to inherit a slow form of the gene from both parents in order to be a slow acetylator. About 50 percent of the Caucasian population are slow acetylators. Although being a fast or slow acetylator is a genetic change, researchers determine a person’s acetylation status through a urine test rather than through DNA testing. The person drinks a small amount of caffeine, which is processed by N-acetyltransferase. After five or six hours, the doctor looks for certain chemicals in the urine that indicate that the caffeine has been processed. If only a small percentage has been processed, then the person is considered a slow acetylator. The fast acetylator phenotype in diabetes mellitus: abnormal prevalence and association with the ABO blood groupsDiabetologia 1984 Aug;27(2):235-237 Pontiroli AE, Mosca A, de Pasqua A, Alcini D, Pozza G
Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer riskRoots I, Drakoulis N, Ploch M, Heinemeyer G, Loddenkemper R, Minks T, Nitz M, Otte F, Koch M Institut fur Klinische Pharmakologie, Freie Universitat Berlin. Klin Wochenschr 1988;66 Suppl 11:87-97
The association of the slow acetylator phenotype with bladder cancerJournal of Medical Genetics, 1983, Vol 20, 330-333 DA Evans, LC Eze and EJ Whibley
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