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The role of xanthine oxidase in thyroid function was studied in the rat in vivo by different approaches. Allopurinol, an inhibitor of xanthine oxidase, was administered by mixing it with a powdered diet (16 mg/100 g body wt per day for 10 days). This treatment significantly reduced the total uptake of iodide and inhibited the organification of iodide in the rat thyroid gland. Thyroid xanthine oxidase and dehydrogenase were almost completely inactivated by tungstate, which was given to rats (100 p.p.m./animal per day in drinking water for 10 days) maintained on a purified diet containing low levels of molybdenum. Under these conditions, no inhibitory effect was observed on synthesis of thyroid hormones. It therefore seemed reasonable to assume that the suppressive effect of allopurinol on the biosynthesis of thyroid hormones is not mediated by xanthine oxidase.
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ABSTRACT
The effects of streptozotocin (STZ) and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on monolayer cultures of rat pancreatic β cells were compared. The intracellular NAD concentration was markedly decreased by both 2 mmol STZ/l and 13·6 μmol MNNG/l, but insulin secretion was decreased significantly only by STZ. The intracellular ATP level decreased rapidly and in a time-dependent manner with STZ, but decreased less on treatment with MNNG: 80% decrease with STZ but only 35% decrease with MNNG in 12 h in the cells exposed to the chemicals for 1 h and then washed thoroughly. STZ decreased oxygen consumption of rat liver mitochondria in a time- and dose-dependent manner and enhanced the generation of hydroxyl radicals (DMPO-adducts). This enhancement was doubled on the addition of succinate as a substrate. Mitochondrial ATP production was also decreased significantly by STZ, but not by MNNG. Thus the marked depletion of intracellular ATP in β cells by STZ seems to be due mainly to a direct effect on mitochondrial production. From these results, we suggest that the cytotoxic effect of STZ in pancreatic β cells is due to a reduction in the intracellular level of ATP, rather than of NAD.
Journal of Endocrinology (1990) 127, 161–165
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ABSTRACT
Exposure of rat pancreatic β cells in monolayer culture to 2 mmol streptozotocin (STZ)/1 for 1 h followed by thorough washing inhibited their uptake of [14C]nicotinamide and [3H]2-deoxyglucose ([2H]2-DG) to about 50% and also reduced the intracellular ATP concentration to 50% of that in control cells. These changes were not due to a lethal cytotoxic effect of STZ, because cell viability, as estimated by succinic dehydrogenase activity, was 90% of that of control cells. Oligomycin and carbonylcyanide-m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation, caused a dose-dependent decrease in intracellular ATP concentration while maintaining high cell viability. These ATP-depleted cells showed a decrease in insulin release and an inhibition of the uptake of [14C]nicotinamide and [3H]2-DG in a dose-dependent manner. Therefore oligomycin and CCCP reproduced the same effects as those found in β cells treated with STZ. These results suggest that the uptake of nicotinamide and 2-DG by β cells might be regulated by their intracellular ATP concentration. The decreased uptake of nicotinamide in ATP-depleted β cells caused by STZ might explain the lack of protective effect of nicotinamide against STZ cytotoxicity when administered after the latter. Furthermore, the radiotracer experiments demonstrated that the transport of nicotinamide by intact β cells was inhibited in a dose-dependent manner by 2-DG and vice versa, i.e. the transport of 2-DG was inhibited by nicotinamide. These findings suggest the existence of a common transport mechanism in β cells responsible for the uptake of nicotinamide and 2-DG, the transport of which is known to occur by facilitated diffusion.
Journal of Endocrinology (1991) 131, 135–138
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ABSTRACT
Ethylidene glucose (4,6-O-ethylidene glucose; EG) is known to bind the outer surface of the glucose transporter in the membranes of human erythrocytes and other mammalian cells. If a glucose transport system is present on pancreatic β cells and recognizes the glucose moiety of streptozotocin (STZ), EG should protect β cells from the cytotoxicity of STZ when it is administered with STZ. This possibility was examined in in-vivo experiments in rats. When EG and STZ were injected into rats together the animals did not become diabetic, as judged by (1) their blood glucose levels, (2) response in a glucose-tolerance test, and (3) insulin secretion in response to feeding. These results suggest that there is a glucose transporter present in β cells and also the transport of streptozotocin into β cells through this system.
J. Endocr. (1987) 112, 375–378
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The pituitary-specific POU-homeodomain transcription factor, Pit-1, is known to regulate the expression of the GH gene in somatotropes, prolactin (PRL) in lactotropes, and TSH in thyrotropes. It is not normally expressed in corticotropes or gonadotropes. We addressed the question of whether exogenous Pit-1 was sufficient to induce ectopic transcription of the GH gene in the corticotropic cell line, AtT-20, or the gonadotropic cell line, alpha T3-1. A fusion gene composed of enhanced green fluorescent protein gene and human Pit-1 cDNA was transfected into AtT-20 and alpha T3-1 cells. The endogenous mouse GH mRNA was induced in three of nine AtT-20 cell lines and one of three alpha T3-1 cell lines containing the fusion gene. A small amount of GH protein was also detected in these cell lines. These data indicate that transfected Pit-1 is capable of inducing transcription of the GH gene in AtT-20 cells and alpha T3-1 cells. These data also suggest that synergistic co-factors might be required to transcribe the GH gene effectively for translation into GH protein. Furthermore, our findings support the hypothesis that the function of anterior pituitary cells is determined by the combinatorial action of specific transcription factors.