Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate.
1. We have shown previously that the D- and L- enantiomers of isoidide dinitrate (D-IIDN and L-IIDN) exhibit a potency difference for relaxation and cyclic GMP accumulation in isolated rat aorta and that this is related to preferential biotransformation of the more potent enantiomer (D-IIDN). The objective of the current study was to examine the effect of the flavoprotein inhibitor, diphenyleneiodonium sulphate (DPI), on the enantioselectivity of IIDN action. 2. In isolated rat aortic strip preparations, exposure to 0.3 microM DPI resulted in a 3.6 fold increase in the EC50 value for D-IIDN-induced relaxation, but had no effect on L-IIDN-induced relaxation. 3. Incubation of aortic strips with 2 microM D- or L-IIDN for 5 min resulted in significantly more D-isoidide mononitrate formed (5.0 +/- 1.5 pmol mg protein(-1)) than L-isoidide mononitrate (2.1 +/- 0.7 pmol mg protein(-1)) and this difference was abolished by pretreatment of tissues with 0.3 microM DPI. DPI had no effect on glutathione S-transferase (GST) activity or GSH-dependent biotransformation of D- or L-IIDN in the 105,000 x g supernatant fraction of rat aorta. 4. Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 microM DPI significantly inhibited D-IIDN-induced cyclic GMP accumulation, but had no effect on L-IIDN-induced cyclic GMP accumulation. 5. In the intact animal, 2 mg kg(-1) DPI significantly inhibited the pharmacokinetic and haemodynamic properties of D-IIDN, but had no effect L-IIDN. 6. These data suggest that the basis for the potency difference for relaxation by the two enantiomers is preferential biotransformation of D-IIDN to NO, by an enzyme that is inhibited by DPI. Given that DPI binds to and inhibits NADPH-cytochrome P450 reductase, the data are consistent with a role for the cytochromes P450-NADPH-cytochrome P450 reductase system in this enantioselective biotransformation process.
Ratz
J D
JD
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.
McGuire
J J
JJ
Bennett
B M
BM
D000368:Aged; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009861:Onium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013402:Sugar Alcohols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D009861:Onium Compounds; D013402:Sugar Alcohols; D014665:Vasodilator Agents; C002589:isoidide dinitrate; C007517:diphenyleneiodonium; D005982:Glutathione Transferase; D006152:Cyclic GMP