Glutathione S-transferase mu polymorphism does not explain variation in nitroglycerin responsiveness.
Haefeli-WE; Srivastava-N; Kelsey-KT; Wiencke-JK; Hoffman-BB; Blaschke-TF
Clin Pharmacol Ther 1993 Apr; 53(4):463-468
To determine whether the considerable interindividual Variability in nitroglycerin-induced venodilation in humans is related to the polymorphic expression of the mu class of glutathione S-transferase (GST mu). Recently vascular glutathione S-transferase (EC 188.8.131.52) of the mu-class (GST mu), a polymorphic group of enzymes present in only about 60% of the population, have been identified and shown in vitro to possess High metabolic activity toward nitroglycerin. Their clinical relevance is unknown. Dose-response relationships to nitroglycerin were constructed in vivo measuring changes in compliance of dorsal hand veins in 26 healthy volunteers during local infusion of small amounts of nitroglycerin. Polymerase chain reaction was applied to detect the deoxyribonucleic acid sequence that codes GST mu in whole blood samples. The GST mu isozyme was present in 15 subjects (58%) and deficient in 11 subjects. Values for mean maximum venodilation (Emax) and dose rates producing 50% of Emax (ED50) were not significantly different between the groups with or without GST mu. The respective values were 98% and 103% dilation for Emax and 9 and 16 ng/min for ED50. There was no gender difference in the venodilatory response to nitroglycerin. Subjects lacking GST mu can clearly respond normally to nitroglycerin, and the large interindividual variability in nitroglycerin potency is not related to the expression of this polymorphic enzyme. Intersubject variability is therefore more likely to be the result of differences in the presence or activity of other vascular enzymes or in steps further distal in the venodilatory cascade.
Mutagenesis; Occupational-health; Cardiovascular-system; Genetics; Humans
Terrence F. Blaschke, MD, Division of Clinical Pharmacology, Stanford University Medical Center, Room S-169, Stanford, CA 94305-5113
Clinical Pharmacology & Therapeutics
Harvard University, School of Public Health, Occupational Health Program, Boston, Massachusetts