Chemical Sensitivity Due to Genetic Differences

Genetic variability is one of the major contributors to drug and chemical sensitivity. Genetic variability exists between all individuals to one degree or another. This variation is the basis for all evolutionary change and our biological existence. The source of this variation occurs as DNA in ovum and sperm cells mutates, recombines, and is passed down to our offspring. Some mutations impart the ability to fight disease while others put us at a disadvantage, and others yet seem to impart no obvious changes at all. The passing of genes to our offspring leads to familial genetic traits such as brown hair or even the ability to effectively metabolize carcinogens found in tobacco. The passing of genes over thousands of generations results in genetic traits that reach beyond the immediate family and may extend throughout a nation or race of people. Examples of sensitive subpopulations due to genetic variation are as follows:

Procainamide, hydralazine, dapsone, and caffeine are all partially metabolized through the N-acetylation pathway. Slow N-acetylation has been associated with bladder cancer while fast N-acetylation is associated with colorectal cancer. The incidence of slow acetylators is (1).

Arylamine dyes also increase the risk of bladder cancer through this metabolic pathway (2).

Ethanol, which is found in alcoholic beverages is metabolized at different rates among humans due to genetic variation within the metabolizing enzymes. Ethanol is broken down into water and acetic acid by a two step process:

Alcohol is first converted to acetaldehyde by an enzyme called alcohol dehydrogenase (ADH). This enzyme consists of two subunits. The subunits are encoded at five different gene locations (for example, location a,b,c,d,e). ADH may consist of any two subunits from any of these locations. These are termed 'isozymes' of ADH. It has been found that there is an unusually high rate of enzyme activity when the isozyme contains at least one subunit from location 'b'. This is one basis for variation in ethanol metabolism among genetically diverse people. Unusually high activities of ADH have been found among 85% of the Japanese and Chinese population. The high activity occurs to a lesser degree among caucasians, less than 21%; African Americans, less than 10%; Native Americans, 0%; and Asian Indians, 0% (3).

Next, acetaldehyde is broken down to acetic acid and water by an enzyme called acetaldehyde dehydrogenase 2 (ALDH 2). It has a high affinity for acetaldehyde and will rapidly convert it. 45 - 53% of Japanese, Chinese, and Vietnamese populations are deficient in ALDH 2 activity due to a point mutation; the replacement of one amino acid for another (GLU487 to LYS487) (3).

The rapid conversion of alcohol to aldehyde coupled with the slow conversion of aldehyde to acid can cause a build up of aldehyde in the blood. This results in dilated blood vessels and obvious flushing of the face. The build up of these metabolites can cause severe illness.

Primaquine, and similar drugs used for the treatment of malaria have been shown to cause hemolytic anemia in 10% of African American males in the U.S. This susceptibility arises from lower than average levels of glucose-6-phosphate dehydrogenase enzymes. Sardinians, Sephardic Jews, Greeks, and Iranians have also exhibited severe responses to primaquine at average doses (1). People should be tested before administration of primaquine or similar substances. Adverse effects of drugs are most pronounced in those that metabolize them slowly and this can be due to a lack of enzyme activity.

Family and twin studies show a familial propensity toward the production of small and dense low-density lipoprotein (LDL), which, is an indicator for high risk of coronary heart disease. There is also evidence that small, dense LDL predicts non-insulin-dependent diabetes mellitus (4). Consumption of fats and salt can further enhance the production of LDL.

Correlations have been made between tobacco induced lung cancer and differences in the primary structure of a P450 (CYP1A1) gene. The gene codes for a P450 enzyme which our bodies use to metabolize chemical carcinogens found in tobacco (5,6).

Deficiencies in serum alpha-1-antitrypsin can leave individuals susceptible to alveolar destruction and pulmonary emphysema from sensitivity to air pollutants such as ozone (1).

Individuals with hereditary blood disorders like sickle cell anemia are sensitive to the effects of benzene, cadmium, and lead which, enhance susceptibility to anemia (2).

Succinylcholine is often used as a muscle relaxant prior to surgery. The duration of this drug is usually just a few minutes but, there is a sub-population in whom succinylcholine has a very long lasting effect, sometimes for hours. Correlation's have been made between this effect and very low activity of the plasma enzyme pseudocholinesterase, which breaks down succinylcholine and therefore terminates its action. Tests for sensitivity are available.

Phenylketonuria is a disease associated with the inability to fully metabolize excess amounts of the amino acid phenylalanine. Phenylketone is excreted in urine as an indicator for this condition. All babies born in U.S. hospitals are tested at birth for this disease, which can cause progressive brain damage. Dietary restriction of foods and drinks containing phenylalanine can control this illness. It should be noted that the artificial sweetner aspartame contains this amino acid.

Deficiencies in enzyme activity can be measured in some cases by measuring the ratio of metabolic products to the parent drug in the urine. In other cases individuals can be tested via a blood test (1).

 

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References

1. Goodman & Gilman's The Pharmacological Basis of Therapeutics. Ninth Ed. Edit. by Molinoff and Ruddon. McGraw-Hill, New York.

2. Principals and Methods of Toxicology. Second Edit. edited by A. Wallace Hayes. Raven Press, New York.

3. Casarett & Doull's Toxicology: The Basic Science of Poison. 5th Ed. Edited by Curtis D. Klaassen. McGraw-Hill, New York. pp. 125-128.

4. Austin MA. 1996. Genetic epidemiology of dyslipidaemia and atherosclerosis. Annals of Medicine, Oct. 28(5):459-63.

5. Kawajiri K., Nakachi K., et al. 1993. The CYP1A1 gene and cancer susceptibility. Critical Reviews in Oncology/Hematology, Feb. 14(1):77-87.

6. Ikawa S., Uematsu F., et al. 1995. Assessment of cancer susceptibility in humans by use of genetic polymorphisms in carcinogen metabolism. Pharmacogenetics, 5 Spec No. S154-60.

This page was prepared by Theresa L. Pedersen and Berna , UCD EXTOXNET FAQ Team. August 1997.