Student Research: Jennifer Reasoner

, , 1993
Faculty Advisor: Curtis J. Omiecinski

Genetic Expression of CYP2D6 (Debrisoquine Hydroxylase) and Epoxide Dydrolase: Studies Examining Their Potential Association with Parkinson's Disease


Abstract

Parkinson's Disease is characterized by a degeneration of the dopaminergic neurons in the substantia nigra and leads to symptoms such as tremor, rigidity, difficulty in moving, and an expressionless face. The etilogy of the disease is unknown, but generally is attributed to normal aging, environmental insults, and possibly genetics. Since a number of chemical exposures appear to initiate the disease process, interest has been generated concerning the potential role of enzymatic detoxification in the disease etiology. This pilot study was designed to determine if defects in two important biotransformation enzymes, cytochrome P450 2D6 (debrisoquine hydroxylase) and microsomal epoxide hydrolase, are associated with an increased risk of Parkinson's disease.

Epidemiological studies have indicated a possible association between the poor debrisoquine metabolizer phenotype and increased risk of Parkinson's Disease. This study utilized DNA based analyses to determine the genotypes of 28 Parkinson's patients and 22 controls, enabling the determination of poor metabolizer individuals. The results suggested a 2.61-fold (95% CI 0.254-26.8) increased risk of Parkinson's disease among poor metabolizers of debrisoquine.

Microsomal epoxide hydrolase is responsible for the detoxification of many toxicologically relevant arene oxides and aliphatic epoxides. A defect in this enzyme system can conceivably lead to accumulation of deleterious metabolites resulting in severe toxicological outcomes such as teratogenesis, as proposed in fetal hydantoin syndrome. This portion of the project was undertaken to determine if an association exists between epoxide hydrolase activity or genotype, and Parkinson's disease.

Epoxide hydrolase activity was measured in lymphocytes from cases and controls and, in parallel assays, DNA was analyzed for two variant genotypes. The results indicated that there was no association with either epoxide hydrolase enzyme levels or genotypes among Parkinson's disease patients and controls.