Potentiation of EPN-induced inhibition of liver microsomal carboxylesterase by addition of liver cytosol from 6-aminonicotinamide-treated, starved rats.
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Addition of liver cytosol from 16 hr-starved rats treated with 6-aminonicotinamide to rat liver microsomes caused potentiation of the anti-carboxylesterase action of ethyl-p-nitrophenyl phenylphosphonothioate (EPN). This was not found when liver cytosol from non-pretreated rats after 16 hr-starvation was used. This potentiation of EPN-induced inhibition of carboxylesterase may be, at least in part, explained by the fact that treatment of rats with 6-aminonicotinamide resulted in a significant increase in NADPH level in liver cytosol which, in turn, stimulated formation of an EPN oxygen analog, a potent inhibitor of carboxylesterase, through cytochrome P-450-coupled monooxygenase. (+info)
Inhibition of glucose reabsorption induced by 6-aminonicotinamide in the rat kidney.
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The relationship between natriuresis and glucosuria produced by administration of 6-aminonicotinamide (6-AN), was investigated in the rat. After intraperitoneal administration of 6-AN (75 mg/kg), urine was collected at intervals of 2 hours using a metabolic cage for assays. Sodium and glucose were excreted maximally into the urine at 2 to 4 and at 4 to 6 hours, respectively, after the administration of 6-AN, with a time delay being recognized between sodium and glucose in the peaks of their urinary excretions. This dissociation of the patterns on the urinary excretion between sodium and glucose led to the following conclusion that the natridiuresis induced by 6-AN was not mainly ascribed to the osmotic diuresis for glucose, but to the direct effect on the sodium transport in the kidney. Furthermore, additional experiments were carried out by loading animals with glucose after administration of 6-AN. The tolerance for glucose in the body was clearly depressed in rats in the 6-AN group, while no significant difference in the renal threshold concentration for glucose was shown in either group. The renal tubular transport maximum for glucose was also depressed in the 6-AN group. It is, accordingly, speculated that the glucosuria induced by 6-AN was not only due to the hyperglycemia, but also due to the decreased capacity of the renal tubular reabsorption for glucose. (+info)
Inhibitory effect of 6-aminonicotinamide on the renal transport of para-aminohippurate in the rat.
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In this study, we investigated the effect of 6-aminonicotinamide (6-AN), a typical potent inhibitor of the pentose phosphate pathway, on the renal transport of para-aminohippurate (PAH) in the rat. The contents of adenosine-triphosphate (ATP) and 6-phosphogluconate (6-PG) in the kidney were measured at intervals of 2 hours after the administration of 6-AN (75 mg/kg body weight, i.p.). It was found that the 6-PG content in the kidney rapidly increased and reached a plateau at the fourth hour after the administration, with this level being maintained up to the eighth hour. In contrast, the ATP content was found to remain normal up to the sixth hour, after which it significantly decreased as time elapsed. Furthermore, additional experiments were carried out by loading the rat with a high concentration of PAH solution at 6 hours after the administration of 6-AN. The renal tubular secretion maximum for PAH was significantly depressed in the 6-AN group in comparison to the control. These results suggest that this depression in renal PAH secretion capacity was partially due to the inhibition of the pentose phosphate pathway in the kidney, but not due to the change of renal ATP level. (+info)
Absence of response of chick embryonic limb to the growth stimulatory effect of parathyroid hormone in vitro after exposure to 6-aminonicotinamide in ovo.
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The biochemical effect of a nicotinamide analogue, 6-aminonicotinamide (6-AN), on developing chick embryonic femur was studied. Growth of femur from 9-day-old embryos that had been exposed to 6-AN for 5 days in ovo was not stimulated by PTH in an in vitro culture system. PTH caused a much smaller increase in the cyclic-AMP content in 6-AN-treated femur than in control femur. However, dibutyryl cyclic-AMP stimulated growth of 6-AN-treated femur. A defect in response of 6-AN-treated femur to the growth stimulating action of PTH may explain the production of micromelia by 6-AN. (+info)
The effect of 6-aminonicotinamide on limb development.
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The morphological effect of the nicotinamide analogue 6-aminonicotinamide on the development of the embryonic chick limb was studied, with special reference to muscle, cartilage, feather germ formation, and ossification. No evidence was found to support theories of control of differentiation by nicotinamide-like substances, although the effect of nicotinamide analogues has often been quoted as evidence for such theories. However, the effect of 6-AN in shortening the limb provides an opportunity to study the interaction of various tissues in normal growth and development, and the results are used to shed further light on the processes involved in muscle splitting, and feather germ formation. (+info)
Acute nicotinamide deficiency in the pig induced by 6-aminonicotinamide.
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Pigs given intraperitoneal injections of 6-aminonicotinamide developed a syndrome similar to a natural disease found in Queensland. Focal lesions, involving mainly destruction of glial cells, developed in the intermediate grey matter of the cervical and lumbar enlargement of the spinal cord. There was widespread vacuolation of spinal cord white matter. The glial cell loss was repaired. We suggest that natural acute nicotinamide deficiency can occur if a threshold dose of an antimetabolite of nicotinamide is absorbed over a short period of time. (+info)
Alterations of chondroitin sulfate synthesized by chick embryo cartilage cultured in the presence of 6-aminonicotinamide.
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Treatment of day-4 chick embryos with 6-aminonicotinamide (6-AN) impairs limbs chondrogenesis and produces micromelia. Interference with limb cartilage development may be related to decreased NAD-dependent synthesis of ATP due to the fact that chondrogenesis is dependent upon anaerobic metabolism. To better understand the effect of 6-AN on chondrogenesis, isolated cartilage epiphyses from day-11 chick embryos were treated in vitro. Sulfate incorporation into total glycosaminoglycans of treated epiphyses was 30% of control. Incorporation of [3H]glucosamine was normal. Fractionation by gel chromatography showed that 40% of the glycosaminoglycans synthesized by treated cells had a molecular weight of less than 15000 compared with 5% of that of the control. A decrease in amount of chondroitin 6-sulfate, an increase of chondroitin 4-sulfate and no change in amount of unsulfated polysaccharide were observed. These results suggest that, upon exposure to 6-AN, chondrocytes produce shorter than normal chondroitin sulfate chains that are preferentially sulfated in the 4 position. Since endochondral bone formation plays an integral role in growth and development of the limb, a defect in production of chondroitin sulfate, a major constituent of cartilage matrix, appears to be involved in 6-AN-induced micromelia. (+info)
Impaired energy metabolism as an initial step in the mechanism for 6-aminonicotinamide-induced limb malformation.
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The analogue and antagonist of nicotinamide, 6-aminonicotinamide (6-AN), impairs cartilage formation and results in shortening of the limbs when administered to chick embryos. Studies have shown that 6-AN forms an abnormal NAD analogue which inhibits the activity of NAD-dependent enzymes associated with production of ATP. To determine if an effect on ATP synthesis might be associated with the mechanism of teratogenesis in the chick embryo, ATP levels of cartilage from day-8 chick embryos treated in vitro were assayed in relation to biosynthesis of protein, DNA and chondroitin sulfate. Incorporation of 35SO4= was inhibited by 6 h or treatment with 10 microgram/ml of 6-AN, whereas incorporation of [3h]thymidine and [3H]amino acid was not inhibited until 12 h. Incorporation of [3H]glucosamine was increased at all treatment times. A decrease in the level of ATP preceded any detectable inhibition of precursor incorporation. These results are consistent with the hypothesis that 6-AN inhibits chondroitin sulfate synthesis through a reduction in the level of ATP in chondrocytes. (+info)