Genetic 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. () and Evans et al. () 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.
In 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 groups
Diabetologia 1984 Aug;27(2):235-237
Pontiroli AE, Mosca A, de Pasqua A, Alcini D, Pozza G
- The acetylator phenotype and ABO blood groups were evaluated in 55 normal subjects and in 156 diabetic patients [61 with Type 1 (insulin-dependent) diabetes and 95 with Type 2 (non-insulin-dependent) diabetes]. The prevalence of fast acetylators was significantly higher in the Type 1 diabetic patients (53%) than in the control subjects (29%). In the Type 2 diabetic patients the prevalence was 39%, and thus not significantly different from the control or Type 1 diabetic groups. In the Type 2 diabetic patients, but not in the control or in the Type 1 diabetic subjects, an association between the fast acetylator phenotype and the B blood group was found.
Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer risk
Roots 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
- Bronchogenic carcinoma is closely associated with cigarette smoking although additional environmental or individual factors might regulate a person's susceptibility to that disease. As a third genetic host factor the AB0 blood group frequencies were evaluated in 263 lung cancer patients. The frequency ratio of A/O was significantly higher as compared to 41,423 blood donors (odds ratio 1.37, 95% confidence limits 1.02-1.84, P less than 0.05). A/O tended to be especially high in young patients not older than 50 years. The ratio B/O in bronchial cancer was significantly higher than expected. The results suggest that the debrisoquine hydroxilator status might have an impact on an individual's susceptibility to lung cancer. This association is either a weak one and/or is restricted to certain histological cancer types or to patients with certain characteristics. The acetylator phenotype could not be established as a risk factor, whereas AB0 blood groups seem to influence lung cancer susceptibility.
The association of the slow acetylator phenotype with bladder cancer
Journal of Medical Genetics, 1983, Vol 20, 330-333 DA Evans, LC Eze and EJ Whibley
- There is an association between exposure to aromatic amines and the development of bladder cancer. Aromatic amines such as are known to occur in tobacco smoke are polymorphically acetylated. One hundred bladder cancer patients have been acetylator phenotyped. Only three of them were non-smokers at the time of diagnosis. This new series, together with four previous series (each with its own control), have been statistically analysed together. The results show a significant association between the slow acetylator phenotype and bladder cancer. The slow acetylator phenotype is associated about 39% more with bladder cancer than is the rapid acetylator phenotype. This association can be interpreted in one of two ways: (1) rapid acetylators may be protected against developing bladder cancer because they are better able to render amines non-carcinogenic by acetylation, or (2) slow acetylators have greater survival with bladder cancer than rapid acetylators. Further evidence will be required to differentiate between these alternatives.