Menadione Nicotinamide Bisulfite Is a BÃƒÂ®oactÃƒÂ®ve Source of ...

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740 ODUHO ET AL. intake and gain:feed ratio (Table 3). Responses at 5 mg/kg nicotinamide were far lower (P < 0.01) than those obtained when 30 mg/kg nicotinamide was sup plemented. Hepatic NAD + NADH concentrations were low in chicks fed the basal diet, but they in creased (P < 0.05) upon adding 5 mg/kg nicotinamide from either nicotinamide or MNB. Multiple linear regression of weight gain (g) as a function of nicotinamide intake (mg) resulted in a good fit (R = 0.98), with the MNB slope being 87% of the slope value for nicotinamide (Fig. 2). Regression coefficients (i.e., slopes), however, were not significantly different (P > 0.05) between the two sources of nicotinamide. Acute toxicity of menadione nicotinamide bi sulfite. Single crop intubations of MPB or MNB at menadione doses of 800 mg menadione/kg body weight or lower did not cause mortality, nor was growth depressed during the subsequent 14-d obser vation period (Table 4). With a dose of 1600 mg/kg body wt, however, 3 of 12 chicks (25%) receiving MPB and 2 of 12 chicks (17%) receiving MNB died in the first 2 d following dosing. This dose of menadione from MNB but not MPB caused a depression in weight gain, feed intake and gain:feed ratio during the 14-d post-dosing period. Chronic toxicity of menadione nicotinamide bi sulfite. Pharmacologie doses of MNB or MNB provided in the diet at levels up to 6000 mg/kg mena dione resulted in no mortality during the 14-d feeding period. At 6000 mg/kg menadione, both sources of menadione depressed (P < 0.05) gain, feed intake and gain:feed, but only MNB depressed blood hemoglobin concentration (Table 5). At 3000 mg/kg menadione, MPB produced no morbidity, but MNB depressed all measures of chick performance. DISCUSSION Menadione nicotinamide bisulfite is an organic salt of two vitamins, menadione bi sulfite and nicotinamide (Fig. 1). According to the manufacturer (Vanetta SPA), MNB, a pale yellow powder, has a melting point of 182Â°C,a pH range of 1 to 3.5 and a water solubility (25Â°C)of 19 g/L. The one-stage prothrombin time chick bioassay (Quick 1957) is considered the most sensitive assay for biopotency of menadione compounds (Augustine 1985, Griminger 1965, Kindberg and Suttie 1989). In our hands the prothrombin time assay worked far better (i.e., better linearity) with thromboplastin iso lated in our laboratory from chicken brain than was the case with purchased rabbit thromboplastin. This agrees with results reported by Griminger (1962). Griminger (1965) and Griminger and Donis (1960) used a vitamin K-assay diet similar to that used herein, and their 21-d-old female chicks appeared to be more deficient in vitamin K than was the case with 0.5 SupplementalNicotinamideIntake (mg/14d) FIGURE 2 Multiple linear regression of weight gain (Y in g) on supplemental nicotinamide intake [X in mg) from nicotinamide (X, *) or MNB (X2, +): Y = 79.3 + 72.7 (Â±5.3)X\ + 63.2 (Â±5.7)Xi, R = 0.98. our unsupplemented male chicks. They used sulfaquinoxaline (2 g/kg) to minimize gut synthesis of vitamin K. We used 2 g/kg sulfathiazole in our vitamin K-deficient diet, and this sulfa drug may have been less effective than sulfaquinoxaline in minimizing gut synthesis of the vitamin. In Griminger's (1965) work, MSBC was 74% as effective as MPB in furnishing bioavailable menadione. In our study (Table 4), MPB and MNB were equally effective in furnishing bioavailable menadione. Based upon prothrombin times of 17 to 19 s at 400 Mg/kg menadione (Table 2), with normal prothrombin times for chickens assumed to range from 12 to 25 s (Smith and Russell 1984), it would appear that the NRC (1984) estimate of 500 Mg/kg for a vitamin K requirement of broiler chickens is a reasonable es timate of the true requirement. Growth bioassays in chicks work well to establish niacin activity of test ingredients (Baker et al. 1973 and 1976, Jacob and Swenseid 1990), but if the test sources contain tryptophan as well as nicotinic acid or nicotinamide, it is difficult to separate niacin responses from tryptophan responses (Baker 1986). Our niacin assay diet contained corn, corn gluten meal and casein. We assumed that nicotinic acid would be only 20% available in corn and corn gluten meal (Darby et al. 1975, Yen et al. 1977) and that bioavailable tryptophan would be relatively low in these ingredients as well (Yen et al. 1971). We were therefore surprised that the niacin assay diet, when adequately fortified with nicotinamide, would not re spond to supplemental tryptophan. Regardless, the diet responded markedly to nicotinamide addition, and the fourfold growth response obtained to addition of 30 mg/kg nicotinamide (Table 3) suggested that lower doses of nicotinamide would result in linear Downloaded from jn.nutrition.org by guest on April 2, 2013
Source0NANANAMNBMNBPooledSupplemental MENADIONE NICOTINAMIDE BISULFITE 741 TABLE3 Performance of chicks fed diets with graded levels of nicotinamide (Assay 2)1 nicotinamideLevelmg/kg02.55.030.02.55.0SEMWeight gain2731361732641081625Feed intake2g/14 NAD NADH3nmol/g + d1682272753642112575Gain:feed2g/kg43659962972551263016Hepatic liver140â€”215â€”â€”24517 'Values are means of four replicate pens of four male chicks during the period 8 to 22 d posthatching; average initial weight was 75 g. For hepatic NAD + NADH, only chicks fed the basal niacin assay diet and those with 5 mg/kg nicotinamide |NA) from NA and menadione nicotinamide bisulfite (MNB) were sampled at d-22 posthatching. 2Linear {P < 0.01) response to NA and MNB; 30 mg/kg NA greater (P < 0.01) than all levels lower. 35 mg/kg NA or MNB greater [P < 0.05) than the basal diet. responses. This was the case (Fig. 2) and the response to nicotinamide from MNB was not significantly different from the response to crystalline nicotinamide. The LD-50 (dose causing 50% mortality) of oral menadione has been reported to be 500 mg/kg body weight in mice (Molitor and Robinson 1940) and 804 mg/kg in chicks (Ansbacher et al. 1942). An oral dose level of 750 mg/kg body weight was nonlethal for chicks. In our acute toxicity study, oral menadione at 800 mg/kg body weight was nonlethal when mena dione was provided as either MNB or MPB; even at 1600 mg/kg menadione, mortality was 25% or less (Table 4). Chronic toxicity studies involving menadione ap parently have not been conducted in avians (NRC TABLE 4 1987). Daily oral doses of 350 mg/kg body weight as menadione over a 30-d period have been observed to depress hemoglobin and blood erythrocyte count in young rats (Molitor and Robinson 1940). Daily oral doses of 500 mg/kg body weight were lethal to rats (Molitor and Robinson 1940), while in this study a dose level of 6000 mg/kg diet over 14 d (equivalent to daily doses of approximately 1000 mg/kg body weight) were nonlethal to young chicks. Avians thus appear to be more tolerant than mammals to either acute or chronic pharmacologie dose levels of mena dione. Although not apparent in mortality data, high levels of MNB were not as well tolerated as high levels of MPB in terms of morbidity criteria (Tables 4 Acute toxicity study: performance of chicks fed a corn-soybean meal diet with an acute oral dose of menadione dimethylpyrimidinol bisulfite (MPB) or menadione nicotinamide bisulfite (MNB) (Assay 3/* Menadione dose2mg/kg wt0100200400800 body d247266244240 intakeMPB395381396403 MNB663656654667 MNB%00000 16003Pooled 211Feed 403MNB3903914163763813579Gain:feedMPB 615g/kg63819632639649630 591MortalityMPB 250000 17 SEMWeightMPB2492622502592692489gainMNBg/14 'Data represent means of three pens of four chicks during the period 8 to 22 d posthatching; average initial weight was 65 g. 2A single crop intubation was given on d 8 posthatching. 31600 mg/kg body wt of menadione from MNB depressed (P < 0.05) weight gain, feed intake and gain:feed. Downloaded from jn.nutrition.org by guest on April 2, 2013
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