CYP2D6, NAT2, and CYP2E1 genetic polymorphisms in nonagenarians

A. G. AGUNDEZ, INMACULADA RODRIGUEZ1, MANUELA OLIVERA, JOSE MARIA LADERO2, A GARCIÁ, JOSÉ M. RIBERA, and JULIO BENÍTEZ 

Department of Pharmacology, School of Medicine, University of Extremadura, Badajoz, Spain
Services of Geriatrics and Gastroenterology of the San Carlos University Hospital, Medical School, Complutense University, Madrid, Spain

Address correspondence to: J. M. Ladero.

Abstract:

Background: Enzymatic polymorphisms that affect the metabolic disposition of xenobiotics may modulate the rate of activation or deactivation of carcinogens and other toxic environmental chemicals. Therefore, these polymorphisms may influence the risk of suffering from some types of cancer and other degenerative diseases that are incompatible with longevity.

Patients: 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, 18.4) 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.

Conclusion: 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.

Keywords: longevity, CYP2D6, CYP2E1, NAT2, cytochrome P450, acetylator, polymorphisms

Introduction:

Another possible link between genetic polymorphisms and longevity is the association of several forms of cancer with genetic polymorphisms of enzymes that metabolize carcinogens [6]. There are several genetic polymorphisms inherited as single Mendelian traits that affect the function of enzymes involved in the activation or deactivation of environmental carcinogens. The three polymorphisms studied here have been linked to developing some common types of cancer [6-9], and CYP2D6 is also linked to the risk of early-onset Parkinson's disease [10]. We have studied the distribution of these enzymatic polymorphisms in a group of nonagenarians to see if there are any differences between this group and younger people that would suggest a role in determining human longevity. These factors are under genetic control. Cardiovascular consequences of atherosclerosis and cancer are the two main causes of death in the post-reproductive period. Genetic polymorphisms affecting the structure or function of lipoproteins have been linked to accelerated atherosclerosis and hence to a shorter life expectancy. Modifications in the apo-AI-CIII-AIV cluster [1] may have such an effect; moreover, carriers of the e4 allele of apo E rarely reach advanced ages [2] and show a higher risk of developing Alzheimer's [4]. Genes determining a moderate level of lipoprotein may be related to increased longevity [5].

Patients and Methods:

Forty-one patients over 90 (10 males, mean age years, range 90-98) in good general health, who were free of known malignancies or neurodegenerative diseases, were recruited from the San Carlos University Hospital's Geriatric Unit. The control group for NAT2 and CYP2D6 polymorphisms was 217 healthy subjects (128 males, mean age 36.3 years; SD, 12.7). The control group for CYP2E1 genotype included 137 healthy volunteers (116 males, mean age 32 years; SD, 18.4). All control subjects were of the same ethnic (white Spanish) and geographic (the central area of Spain) origin.

The study was approved by the ethics committee of the San Carlos University Hospital (Madrid), under the guidelines of the 1975 Declaration of Helsinki. Patients and controls gave informed consent to be included in the study.

Results: