Molecular Pharmacology, Vol 12, 291-298, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Formation in Vitro and in Vivo of the Isonicotinic Acid Hydrazide Analogue of Nicotinamide Adenine Dinucleotide by Lung Nicotinamide Adenine Dinucleotide Glycohydrolase

¹ Pharmacology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

Mammalian lungs have relatively high levels of NAD glycohydrolase activity. The enzyme in this organ appears to occur exclusively in membrane fractions with high activities in the 25,000 x g and 105,000 x g sediments. Isolated rabbit pulmonary alveolar macrophages exhibited no enzyme activity, either as intact cells or as sonicated suspensions. The membrane-bound enzyme from rat lung was shown to have a broad pH optimum (5.9-6.9) and low NADP glycohydrolase activity. The enzyme was "insensitive" to isoniazid (INH), and, among a group of congeners tested, only nicotinamide, a reaction product, was a potent inhibitor. Transglycosidase activity in vitro, as measured spectrophotometrically and chromatographically, was observed in the presence of INH. Formation of the INH analogue of NAD in vitro was inhibited by nicotinamide. To examine lung transglycosidase activity in vivo, [¹⁴C]INH was injected intravenously into rats and the lungs were extracted and analyzed for the oxidized nucleotide analogue. Identification of significant levels of isotope covalently linked in the nucleotide support transglycosidase activity in vivo. The half-life of the analogue (t_1/2 60 min) in the lung was approximately twice that of the total organ ¹⁴C decay rate (t_l/2 28 min).

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ACKNOWLEDGMENT The author acknowledges the excellent technical assistance of Mrs. Sandra Gipson.

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