US EPA

2241054 

Journal Article 

The transformation of glyceryl trinitrate and other nitrates by glutathione-organic nitrate reductase 

Needleman, P; Hunter, FE 

1965 

1 

Molecular Pharmacology
ISSN: 0026-895X
EISSN: 1521-0111 

NIOSH/00128897 

1 

1 

77-86 

English 

4378648 

The biotransformation of organic nitrates by glutathione organic nitrate reductase was investigated. In-vitro tests, spectrophotometric and fluorometric assay systems were developed to measure nitrate transformation based on formation of oxidized glutathione (GSSG) and disappearance of triphosphopyridine-nucleotide-hydride (TPNH). For in-vivo tests, albino-rats were given 10 milligrams of test nitrate intraperitoneally, and urine was collected at 24 hours for chromatographic analysis of metabolites. Glyceryl-nitrite (55630) (GTN) was degraded to yield 1,3-glyceryl-dinitrate (GDN), 1,2-GDN, and inorganic nitrite. About 90 percent of the GTN was transformed, and no product inhibition occurred. TPNH consumption equalled nitrite formation. GTN was transformed about 20 times faster than dinitrate esters, which, in turn, were transformed faster than mononitrates. Linear chain polynitrate esters were rapidly transformed, while branched chain alcohol nitrates were slowly transformed. Metabolic products recovered in the urine of treated rats were similar to the products identified in-vitro, indicating comparable transformation processes and pathways. The authors conclude that denitration is the primary route of organic nitrate transformation. The in-vitro assay system can be used successfully to directly and continuously measure product formation through TPNH disappearance.