Summary. A method for determining plasma paroxonase activity using an auto-analyser is described. Frequency distributions for British and Indian subjects show bimodality. A study of 40 British families confirms the presence of a genetic polymorphism with regard to plasma paroxonase activity. Two phenotypes can be defined, controlled by two alleles at one autosomal locus. The frequency of the low activity phenotype is less in the Indian population than in the British population. Malay, Chinese, and African subjects fail to show obvious bimodality.
A key biological puzzle is to understand how a known environmental agent reacts with a genetic polymorphism in such a manner that some subjects of a given phenotype are more prone to develop a particular disorder. Bladder cancers are known to occur at a higher rate in subjects exposed to aromatic amines either in tobacco smoke or in their occupations.' It has been found in both human and rabbit populations that some carcinogenic aromatic amines (for example, amino-fluorene, benzidine, and 2-naphthyl-amine) are polymorphically acetylated by the same N-acetyl-transferase that is responsible for the polymorphic acetylation of a number of drugs.2 3 In this genetic polymorphism slow acetylation is an autosomal recessive phenotype.4 These considerations have led to the suggestion that the two human acetylator phenotypes may differ in their predisposition to develop neoplastic disorders believed to be caused by aromatic amines. This idea is based on an analogy with the now established fact that genetic constitution can predispose to drug toxicity.5 An obvious example to test the hypothesis is bladder cancer.
Trehalase is an enzyme which hydrolyzes the disaccharide trehalose, yielding glucose. It is widespread in nature and found in various human tissues as well as in human plasma. The synthesis and degradation of its substrate trehalose have been considered as being implicated in carbohydrate transport mechanisms. Trehalase activity has been examined in both normal subjects and diabetic patients. In the normal subjects, the frequency histogram of the enzyme activity is bimodal, indicating the existence of genetic polymorphism. The proposed model of a single autosomal locus with two alleles has been verified, with 27% of the population tested belonging to the "low-activity" phenotype and 73% being of the "high-activity" phenotype. Males have higher mean plasma trehalase activity than females. Apparently, the reverse appears to be the case in the diabetic subjects. The mean value for all nondiabetics and that of diabetics were computed and the difference was found to be statistically significant (F = 7.02, N1 = 3, N2 = 56, P less than 0.01). An experiment showed that neither the abnormally high concentration of glucose in diabetics nor any other constituent of the diabetic plasma caused an increase in plasma trehalase activity (t = 0.0724, P greater than 0.10). A Woolf and Haldane test to determine association of diabetes mellitus and plasma trehalase phenotype indicated a highly significant association with the high-activity phenotype (chi 2 = 18.5350, P less than 0.01). Thus the inference is that people with high plasma trehalase activity are more prone to develop diabetes mellitus than people with low enzyme activity.
Sulfamethazine (syn, sulfadimidine) is inactivated by conversion to its N-acetyl derivative. Individuals are phenotyped as either "rapid" or "slow" acetylators. We have tested the validity of this theory in a Nigerian population. The frequency distribution histograms of the percentage acetylsulfamethazine in urine and serum were found to be bimodal, indicating the existence of a genetic polymorphism as observed by earlier workers. A plot of the percentage of the drug acetylated in serum against that in urine of the same individual results in a satisfactory separation of the rapid and slow acetylator phenotypes. An incidence of the slow acetylator phenotype of 41% was observed in the Nigerian population tested. How this observation fits into the hypothesis that the slow frequency of the allele increases from the Arctic Circle toward the Equator is discussed.
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