Growth-promoting Activity of Pyrazinoic Acid, a Putative Active Compound of Antituberculosis Drug Pyrazinamide, in Niacin-deficient Rats through the Inhibition of ACMSD Activity

Abstract

We have recently reported that the antituberculosis drug, pyrazinamide (PZA), caused a significant increase in the conversion ratio of tryptophan to niacin in rats. In the present work, we investigated whether or not pyrazinoic acid (POA), a putative metabolite of PZA, increased the conversion ratio of tryptophan to niacin. Weaning rats were fed with a niacin-free and tryptophan-limited diet (negative control diet), or with the negative control diet supplemented with 0.003% nicotinic acid (positive control diet) or 1% POA (test diet) for 27 days. The growth rate was almost same between the groups fed on the positive control diet and the test diet. Dietary POA significantly increased the conversion ratio of tryptophan to niacin. Although POA did not directly inhibit the activity of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD), the rate-limiting enzyme in the tryptophan-niacin pathway, liver ACMSD activity was only not detected in the test diet group. These results suggest that a derivative of POA metabolized by rats inhibited the ACMSD activity.

Increased Conversion of Tryptophan to Nicotinamide in Rats by Dietary Valproate

“…3). A similar phenomenon has already been reported by using such other chemicals as pyrazinamide, 22,24,27) di(2-ethylhexyl)phthalate (DEHP), 23,26,[28][29][30] and chlofibrate. 21) We assayed the effects on the enzyme activities of these compounds on the Trp-Nam pathway to discover the action point of these chemicals and fatty acid.…”

“…21) We assayed the effects on the enzyme activities of these compounds on the Trp-Nam pathway to discover the action point of these chemicals and fatty acid. The previous paper has reported that the activities of TDO, kynureninase, 2-Py-forming MNA oxidase, and 4-Py-forming MNA oxidase were lower in the groups treated with pyrazinamide, 22,24,27) DEHP, 23,26,[28][29][30] and chlofibrate 21) than in the control group. Similar results were obtained in the present experiment ( Table 3).…”

“…The conversion of Trp to Nam is not constant: it is affected by age, 8) various nutritional factors, 1,[9][10][11][12][13][14][15][16][17] hormones, [18][19][20] and chemicals. [21][22][23][24][25][26][27][28][29][30] Shin et al 31) have reported that the administration to rats of peroxisome proliferators increased the liver NAD concentration by inhibiting liver -amino--carboxymuconate-"-semialdehyde decarboxylase (ACMSD). Our experience of measuring the ACMSD activity has taught us the difficulty of measuring the extent of inhibition by the method used by Shin et al 31) We were however interested in the result that the administration of valproic acid (VPA), one of the peroxisome proliferators, increased the liver NAD concentration, 31) because there have been several reports of such short-chained fatty acids [32][33][34] as sodium acetate, sodium 3-hydroxybutyrate, sodium acetoacetate and dietary fat [35][36][37] affecting metabolism on the Trp degradation pathway.…”

Kynurenine pathway metabolites and suicidality

“…Whereas the detailed regulation of this enzyme is yet to be established, it is known that environmental contaminants (e.g. phthalate esters) and the antituberculosis drug pyrazinamide are capable of inhibiting ACMSD activity, thus increasing the amount of QUIN (Fukuwatari et al, 2004; Fukuwatari et al, 2002). Changes in the nutritional status and the presence of some diseases states, such as diabetes and renal failure, can lead to alteration of ACMSD expression and activity (Egashira et al, 2007; Fukuoka et al, 2003).…”

Effects of Excess Nicotinamide Administration on the Urinary Excretion of NicotinamideN-Oxide and Nicotinuric Acid by Rats

“…1). Numerous factors such as pregnancy, 7) nutrition, [8][9][10][11][12][13][14][15] hormones, [16][17][18][19][20] chemicals, [21][22][23][24][25][26] and experimental models of diseases [27][28][29] affect this conversion from tryptophan to nicotinamide. However, little is known about the association between the nicotinamide intake and tryptophan-nicotinamide pathway.…”