CYP2D6, NAT2 and CYP2E1 genetic polymorphisms in nonagenarians.
BACKGROUND
enzymatic polymorphisms affecting the metabolic disposition of xenobiotics may modulate the rate of activation or deactivation of carcinogens and other toxic environmental chemicals. Hence, these polymorphisms may influence the risk of suffering some types of cancer and other degenerative diseases that are incompatible with extreme longevity.


OBJECTIVE
to establish the distribution of three well known enzymatic polymorphisms that affect the CYP2D6, NAT-2 and CYP2E1 genes and the activity of their enzymatic gene products, involved in the disposition of many xenobiotics, in a group of nonagenarians and in much younger controls.


METHODS
the three genotypes were determined in 41 nonagenarians (10 males, mean age 92.2 years, range 90-98) free of known malignancies or neurodegenerative diseases. The control groups comprised 217 healthy volunteers (128 males, mean age 36.3 years; SD, 12.7) for the CYP2D6 and NAT2 genotypes and 137 (116 males, mean age 32 years; SD, 18.8) for the CYP2E1 genotype.


METHODS
after extraction of DNA from white blood cells, polymerase chain reaction and restriction fragment polymorphism methods were used to identify the allelic variants of the three genotypes.


RESULTS
we found no qualitative or quantitative difference in the mutations underlying the three genetic polymorphisms studied, nor in the expected enzymatic phenotypes. Instead, a close parallelism exists between advanced age and younger groups.


CONCLUSIONS
longevity does not seem to be related to any special configuration of these three polymorphic traits. Comparisons with younger controls may be adequate when studying the distribution of these polymorphisms in diseases affecting old people. No genetically determined differences in the activation of drugs metabolized by these enzymes are to be expected in very old people.
Agúndez
J A
JA
Department of Pharmacology, School of Medicine, University of Extremadura, Badajoz, Spain.
Rodríguez
I
I
Olivera
M
M
Ladero
J M
JM
García
M A
MA
Ribera
J M
JM
Benítez
J
J
D000368:Aged; D000369:Aged, 80 and over / Q000502:physiology*; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008136:Longevity / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012016:Reference Values
D019392:Cytochrome P-450 CYP2E1; D019389:Cytochrome P-450 CYP2D6; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human