Diabetic hyperglycemia is typically accompanied by various protein modifications, indicating hyperglycemic glucotoxicity. Overactivation of poly [adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP-1) has been implicated in the pathogenesis of oxidative stress-related diseases including diabetes and its complications. Furthermore, obesity and diabetes are known to be associated with a substantial risk of chronic liver disease. We have previously reported that thiamine supplementation prevented obesity and diabetes-related liver disease. As a step forward, in the present study, we focus on hepatic ADP-ribosylation that reflects PARP-1 activation and an increased oxidative stress condition. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomly divided into the following groups: thiamine-supplemented and unsupplemented control groups. The thiamine-supplemented group received 2 g of thiamine/L of drinking water for 33 weeks. ADP-ribosylated protein expression was analyzed in the livers of OLETF rats using Western blotting. Moreover, the fasting blood glucose level was measured in these rats. The obese diabetic OLETF rats exhibited high ADP-ribosylated protein expression in the liver. Interestingly, hepatic ADP-ribosylated protein expression and fasting blood glucose levels were lower in the thiamine-supplemented OLETF group than in the control OLETF group. These results suggest that thiamine supplementation attenuates oxidative stress by inhibiting hepatic ADP-ribosylation in OLETF rats. The beneficial effect of high-dose thiamine on oxidative stress-related diseases could be attributed to its inhibitory effect on PARP-1 activation, in addition to its role as a coenzyme. Furthermore, we found that thiamine supplementation prevented fasting hyperglycemia, suggesting that high-dose thiamine modifies the hepatic glucose metabolism and obesity-induced hepatic insulin resistance.
Glycidol fatty acid esters (GEs) are food process contaminants detected in edible oils. It has been thought that glycidol is released from GEs by lipase in vivo, and shows genotoxicity. While DNA damage from glycidol has been reported, there is very little information on the DNA damaging potency of GEs in vivo. Therefore, we estimated DNA damage of glycidol and glycidyl oleate, which is one type of GEs, using the standard comet assay and a formamidopyrimidine glycosylase(Fpg)-modified comet assay. ICR male mice were orally administrated glycidol and glycidyl oleate (1.0 and 2.0 mmol/kg body weight) at 24 and 3 hr prior to dissection. In the standard comet assay, DNA damage (tail length and % tail DNA) in liver, kidney and blood samples of glycidol-treated groups were increased in a concentration-dependent manner. In Fpg-modified comet assay, glycidol showed DNA damage with higher sensitivity compared with the standard comet assay. DNA damage was not observed in the administration group of glycidyloleate in the standard comet assay. However, in Fpg-modified comet assay, glycidyl oleate showed significant DNA damage in the liver, kidney and blood samples compared with the standard comet assay. In this study, it was revealed that glycidol and glycidyl oleate induce DNA damage, such as oxidative and alkylation damage, recognized by Fpg protein.