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Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate
Author(s) -
Ratz Jodan D,
McGuire John J,
Bennett Brian M
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702268
Subject(s) - biotransformation , chemistry , glutathione , enantiomer , ec50 , pharmacology , potency , biochemistry , in vitro , enzyme , stereochemistry , biology
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. In isolated rat aortic strip preparations, exposure to 0.3 μ M DPI resulted in a 3.6 fold increase in the EC 50 value for D‐IIDN‐induced relaxation, but had no effect on L‐IIDN‐induced relaxation. Incubation of aortic strips with 2 μ M 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 μ M DPI. DPI had no effect on glutathione S ‐transferase (GST) activity or GSH‐dependent biotransformation of D‐ or L‐IIDN in the 105,000× g supernatant fraction of rat aorta. Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 μ M DPI significantly inhibited D‐IIDN‐induced cyclic GMP accumulation, but had no effect on L‐IIDN‐induced cyclic GMP accumulation. 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. 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.British Journal of Pharmacology (1999) 126 , 61–68; doi: 10.1038/sj.bjp.0702268