PT  - JOURNAL ARTICLE
AU  - R. L. BLAKE
AU  - S. L. BLAKE
AU  - H. H. LOH
AU  - ERNEST KUN
TI  - The Effect of Nicotinamide and Homologs on the Activity of Inducible Enzymes and NAD Content of the Rat Liver
DP  - 1967 Sep 01
TA  - Molecular Pharmacology
PG  - 412--422
VI  - 3
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/3/5/412.short
4100  - http://molpharm.aspetjournals.org/content/3/5/412.full
SO  - Mol Pharmacol1967 Sep 01; 3
AB  - The activity of tryptophan pyrrolase (L-tryptophan:oxygen oxidoreductase, EC 1.13.1.12) and tyrosine transaminase (L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5) of the rat liver increases after intraperitoneal injection of nonphysiological amounts of nicotinamide. Actinomycin D (2 mg/kg), injected 30 minutes prior to nicotinamide, inhibited this effect of nicotinamide. Certain pyridine derivatives related to nicotinamide, such as nicotinic acid, 5-fluoronicotinamide, isonicotinic acid hydrazide, and nikethamide (N,N-diethylnicotinamide) had similar effects by increasing tryptophan pyrrolase activity. Hypophysectomy abolished the induction of enzymes caused by nicotinamide, 5 mmoles/kg (within 6 hr after injection), while hydrocortisone (5.2 x 10-2 mmoles/kg) in hypophysectomized rats increased enzyme activity 10-fold during the same period. Feeding inhibited by 50% the increase of tryptophan pyrrolase by nicotinamide as compared to the rate of induction in fasted animals. On the other hand, induction of tryptophan pyrrolase by hydrocortisone, 5.2 x 10-2 mmoles/kg, did not depend on the nutritional state of the animals. Augmentation of NAD in rat liver following injection of nicotinamide precedes enzyme induction. Starvation increases NAD accumulation from nicotinamide. Actinomycin D has no effect on NAD augmentation from precursors. Newly formed NAD following injection of nicotinamide is almost exclusively localized in the cytoplasmic cell fraction of rat liver. The rate and degree of NAD accumulation following injection of various metabolic precursors of NAD exhibit marked tissue dependent variation. A working hypothesis is proposed, predicting that nicotinamide causes enzyme induction in liver by augmenting NAD levels of adrenals. Increased pyridine nucleotide content of adrenals may then cause an increased synthesis and release of cortical hormones; thus the latter would be the true inducers of liver enzymes. Toxic nicotinamide homologs that do not augment NAD levels, but act as enzyme inducers, may release cortical hormones directly, without contributing to their continued biosynthesis. ACKNOWLEDGMENTS This work was supported by research grants of the American Heart Association, Inc. (66-652), the National Science Foundation (GB-3488), and the United States Public Health Service (R0l-01239-11 and R01-CA-07955-03), and in part by USPHS training grant HE-5251.