Reaction of organic nitrate esters and S-nitrosothiols with reduced flavins: a possible mechanism of bioactivation.
Organic nitrate esters, such as glyceryl trinitrate and isosorbide dinitrate, are a class of compounds used to treat a variety of vascular ailments. Their effectiveness relies on their ability to be bioactivated to nitric oxide (NO) which, in turn, relaxes vascular smooth muscle. Although there have been many biological studies that indicate that NO can be formed from organic nitrate esters in a biological environment, the chemical mechanism by which this occurs has yet to be established. Previous studies have implicated both flavins and thiols in organic nitrate ester bioactivation. Thus, we examined the chemical interactions of flavins and thiols with organic nitrate esters as a means of determining the role these species may play in NO production. Based on these studies we concluded that a reasonable chemical mechanism for organic nitrate ester bioactivation involves reduction to the organic nitrite ester followed by conversion to a nitrosothiol. The release of NO from nitrosothiols can occur via a variety of processes including reaction with dihydroflavins and NADH.
Wong
P S
PS
Department of Pharmacology, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, California 90095-1735, USA.
Fukuto
J M
JM
D001711:Biotransformation; D005486:Flavin Mononucleotide / Q000737:chemistry*; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry; D019803:Glutathione Disulfide / Q000737:chemistry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009243:NAD / Q000737:chemistry; D009566:Nitrates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000737:chemistry; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000493:pharmacokinetics*; D009573:Nitrites / Q000378:metabolism; D009574:Nitro Compounds / Q000737:chemistry; D005996:Nitroglycerin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D009603:Nitroso Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D009609:Nitrous Oxide / Q000737:chemistry; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014664:Vasodilation / Q000187:drug effects
D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009574:Nitro Compounds; D009603:Nitroso Compounds; C116027:S-nitroglutathione; D013438:Sulfhydryl Compounds; D009243:NAD; D009569:Nitric Oxide; C061330:tert-butylthiol; D005486:Flavin Mononucleotide; D005996:Nitroglycerin; D005978:Glutathione; D009609:Nitrous Oxide; D019803:Glutathione Disulfide