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genotypes, respectively. There were no poor meta- bolizers in the study group and only eight (3-7%) in the control group. Although these differences were non- significant, we have calculated the expected preva- lence of poor metabolizers (homozygous for defective CYP2D6 alleles), according Hardy-Weinberg's equi- librium for the prevalence of defect alleles, in both groups. According to this, the expected prevalence for poor metabolizers is 2.5% for cases and 2% for These data are not significantly different from each other and from the actual values shown in the Table 2. Table 3 shows the distribution of the Rsal poly- morphisms of the gene CYP2E1. Again, no significant

morphisms of the gene CYP2E1. Again, no differences, but a narrow parallelism, was found.

Fisher exact or Mantel-Haenszel tests, as appropriate. Calculations were made by using the Epilnfo6 statis- tical software. The null hypothesis was rejected when

Discussion

These results discount any relevant influence of CYP2D6, NAT2 or CYP2E1 genotypes on the prob- ability of reaching an advanced age, at least in the Spanish population. We have performed this study after detecting a significant excess of homozygote CYP2D6 extensive metabolizers (EM) and a sixfold excess of the allele CYP2D6(C) in lung cancer [15], a twofold excess of the CYP2D6QS) allele women with breast cancer [16], a marked excess of

Results

The prevalence of allelic variants (Figure 1), as well the distribution of acetylator genotypes (Table 1) therefore the predicted acetylator phenotypes, were very similar in both groups. Figure 2 and Table 2 the distribution of CYP2D6 allelic variants and

Table |. Distribution of acetylator genotypes

No. (and %) No. of functioning alleles Cases Controls 0 (slow acetylators) 22 (53.7) 117(53.9) 1 (heterozygote rapid acetylators) 16 (390) 83 (38.2) 2 (homozygote rapid acetylators) 3(7.3) 17 (78)

• Nonagenarians • Younger controls CYP2D6wt Mutated defective: Mutated active: CYP2D6A CYP2D6C CYP2D6B CYP2D6L CYP2D6D

Table 3. Distribution of CYP2E1-Rsa\ restriction ment length polymorphisms

The CYP2E1 gene, which codes the synthesis of P4502E1, is affected by several polymorphisms at non- coding regions of the gene locus [20]. However, one of these polymorphisms is located at a regulatory site in the 5' flanking region, in a putative binding region for the transcription factor HNF-1 [7] and probably influences the functional rate of the enzyme [7]. P4502E1 is the main isozyme of the P450 cytochrome oxidase system involved in the metabolism of ethanol and of many other xenobiotics, including some car- cinogens [8]. At present, conclusive data on a relation- ship between CYP2E1-Rsal polymorphism and risk any severe disease have only been shown in patients with liver cancer who were ethanol-abusers [9]. It has been suggested that this polymorphisms could modu- late the risk of liver cirrhosis in ethanol abusers [21, 22], but this has not been confirmed by us [23].

Figure 2. Frequency of major CYP2D6 allelic variants nonagenarians and in younger controls. The assigna- tion as defective or active alleles has been done according published studies [13, 15, 25-29].

homozygote CYP2D6 EMs in patients with hepato- cellular carcinoma [17], an excess of phenotypic slow acetylators among urothelioma patients exposed to

Table 2. Distribution of CYP2D6 genotypes andphenotypes

Taken together, these data suggest that specific combinations of enzymatic polymorphisms could influence the risk of developing some forms of cancer. Nevertheless, patients in this study were not smokers and were not affected by chronic liver disease, that are usually necessary for the development of lung and liver cancers, respectively. Smoking and drinking habits or chronic liver disease are usually incom- patible with extreme longevity due to the high risk of death at an earlier age caused by diseases not related to these polymorphisms (atherosclerosis, chronic bronchitis, extrahepatic organic sequelae of alcohol abuse, etc.). The findings obtained in this comparative study make the selection of subjects for control groups easier for studies on diseases affecting people older than 50, as young healthy people are easier to find and recruit.

Another point raised by this study is that age-related differences in drug response and toxicity cannot be attributed to a different prevalence of functional genes of the studied drug-metabolizing enzymes, namely CYP2D6, CYP2E1 and NAT2, in very aged people. The genes studied here encode enzymes which are responsible for the metabolism of several drugs. These include tricyclic antidepressants, neuroleptics, beta- blockers and other antiarrhythmics (CYP2D6); para- cetamol, chlorzoxazone and ethanol (CYP2E1) and hydrazines, arylamines, pyrazolones, caffeine and

The L2 allele represents an allelic duplication. This patient should be classified as a homozygote extensive metabolizers [13]. homozygote (EMs) cany two functional alleles, Le. wt, C o rL Heterozygote EMs carry only one active allele. Poor metabolizers carry two inactive alleles (A, B or D).

nitrazepam (NAT2) among others. Any genetic selec- tion in older people would determine differences in the metabolism of these drugs, as compared with younger subjects.

5. Berg K. Lp(a) lipoprotein: an overview. Chem Phys Iipids 1994; 67-68: 9-16.

6. Caporaso N, Land! MT, Vineis P. Relevance of polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence. Pharmacogenetics 1991; 1: 4-19.