The association of the slow acetylator phenotype with bladder cancer.

Abstract

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.

Distribution of Alpha-l-Antitrypsin and Haptoglobin Phenotypes in Bladder Cancer Patients

“…The polymorphic enzyme N-acetyltransferase catalyses the detoxication of these substances, and slow acetylation has been shown to play a considerable role in bladder carcinogenesis [Evans et al, 1983;Hanssen et al, 1985], In this respect, the polymorphic plasmaproteins haptoglobin and Pi also seem to be useful genetic markers showing significant associations with bladder carcinogenesis.…”

Meta-analysis of the relationship between slow acetylation of N-acetyl transferase 2 and the risk of bladder cancer

“…A total of 20 case-control studies analyzing NAT2 and the risk of bladder cancer were enrolled in our analysis (Fleiss, 1980;Evans et al, 1983;Hanssen et al, 1985;DerSimonian et al, 1986;Pearce et al, 1989;Horai et al, 1989;Ponder, 1991;Dickersin et al, 1992;Hayes et al, 1993;Greenland, 1994;Smith et al, 1995;Risch et al, 1995;Houlston, 1996;Stanley et al, 1996;Filiadis et al, 1999;Hirvonen, 1999;Hsieh et al, 1999;Brennan et al, 2000) (Table 1). Studies wherein the NAT2 phenotype only analyzed in a patient group or control group were ruled out to prevent bias.…”

“…Several scholars have confirmed an association between bladder cancer risk and N-acetyl transferase-2 (NAT2) slow acetylation (Cartwright et al, 1982;Evans et al, 1983;DerSimonian et al, 1986;Dickersin et al, 1992;Risch et al, 1995;ONS, 1996;Filiadis et al, 1999). However, some studies have failed to prove this relationship, which may be attributed to the statistical difference in sample size.…”

Effects of Ethanol and Phenobarbital on Hemoglobin Adducts Formation in Rats Exposed to Benzidine and Direct Black 38

“…Amines with one amine group such as aniline and 4ABP are more useful when acetylation can be explained in the evaluation of exposure to hemoglobin adducts 17) since the risk for bladder cancer increases when Nhydroxylation increases competitively due to slowly progressing N-acetylation 61,62) . However, it is difficult to explain for toxicity and solubility only with N-acetylation because deacetylation and N-acetylation occur at the same time in amines with more than 2 amine groups such as BZ 29) .…”