Effect of the organophosphorus pesticide diazinon on glucose tolerance in type 2 diabetic rats
Introduction
Organophosphorus pesticides (OPs) are widely used to improve crop productivity and hygienic environments in many developed countries. Sales of diazinon (DZN), one of the OPs, have been legally limited in the United States from December 31 2004, due to its toxicity for human health. However, DZN is commonly used to control a range of crop pests and is also used as a veterinary ecotoparasiticide in Asia, including Japan. Indeed, annual production of DZN-related compounds in Japan between 2003 and 2005 is presented to be about 10 million tons (Nouyaku-Youran, 2006). Although it is well known that primary target of OPs including DZN is acetylcholine esterase (AChE), they have several toxicological effects such as delayed neurotoxicity and/or polyneuropathy caused by inhibition of neuropathy target esterase (Lotti and Moretto, 2005, Quistad et al., 2002, Casida and Quistad, 2004) and hyperglycemia (Seifert, 2001).
Diabetes mellitus (DM) is a chronic metabolic disorder representing an increase in blood glucose levels due to an absolute or relative deficiency of insulin and/or an increase in insulin resistance. A report of Japanese Ministry of Health, Labor and Welfare in 2002 has claimed that 7.4 million of Japanese populations are strongly suspected to suffer from DM. It is reported that DM might modify drug pharmacokinetics by changing hepatic drug-metabolizing enzyme activity (Dixon et al., 1961, Thummel and Schenkman, 1990). We have recently found the possibility that DZN causes high toxicity in streptozotocin-induced type 1 diabetic model rats due to the overproduction of DZN-oxon, which is a major DZN metabolite and a potent inhibitor of AChE, as a result of up-regulation of hepatic CYP1A2 (Ueyama et al., 2007). However, there is no detailed information about the ill-effect of DZN on type 2 diabetic model rats.
It has been reported that DZN induces hyperglycemia (Seifert, 2001) and pancreatitis (Frick et al., 1987) in experimental animals. In the present study, to verify the hypothesis that DZN alters the glucose tolerance in control and diabetic model rats, we investigated the effect of DZN on type 2 diabetic mellitus using Goto-Kakizaki (GK) rats, which are a spontaneous animal model of non-insulin-dependent diabetes (NIDDM) without obesity (Goto et al., 1988).
Section snippets
Chemicals
Glucose and DZN (the purity is 99%) were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan). Citric acid and sodium carboxymethylcellulose (CMC) were purchased from Yoneyama Yakuhin Kogyo Co., Ltd. (Osaka, Japan). Blood glucose level monitor system GLUTEST NEO was kindly donated from Sanwa Kagaku Kenkyusho Co., Ltd. (Mie, Japan). N-Histofine Simple Stain Rat MAX PO (M) was purchased from Nichirei Biosciences (Tokyo, Japan). 5,5′-Dithio-bis-2-nitrobenzoic acid (DTNB),
Biochemical data
Biochemical data are summarized in Table 1. DZN significantly decreased plasma triglyceride levels in both Wistar and GK rats, and decreased plasma total cholesterol levels in Wistar rats, but not GK rats. DZN had no effect on the body weight, total protein, amylase activity and HDL-cholesterol in both rats.
Effect of DZN on OGTT in Wistar and GK rats
Plasma concentration–time curves of glucose in Wistar and GK rats before and after oral administration of glucose are shown in Fig. 1A. There were no significant differences in the fasting
Discussion
We have recently demonstrated that toxicological effect of DZN is enhanced in streptozotocin-induced diabetic model rats due to overproduction of DZN-oxon by increased hepatic drug-metabolizing enzyme activity (Ueyama et al., 2007). GK rats are used as a valuable tool for understanding the pathogenesis of type 2 diabetes and for development of new drugs (Bisbis et al., 1993, Ikeda and Sugiyama, 2001). The novel findings obtained in this study are that DZN impaired glucose tolerance in the type
Acknowledgments
This work was supported in part by a Health and Labor Sciences Research Grant (Research on Risk of Chemical Substances) from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for Scientific Research (19790404, 17310033) from the Japan Society for the Promotion of Science.
References (31)
- et al.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity
Reprod. Toxicol.
(1996) - et al.
Relationship between autonomic dysfunction, insulin resistance and hypertension, in diabetes
Nutr. Metab. Cardiovasc. Dis.
(2005) - et al.
Effect of diacetylmonoxime and atropine on malathion-induced changes in blood glucose level and glycogen content of certain brain structures of rats
Biochem. Pharmacol.
(1982) - et al.
Role of tumor necrosis factor-alpha in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin
Eur. J. Pharmacol.
(2005) - et al.
The carbon monoxide-binding pigment of liver microsomes
J. Biol. Chem.
(1964) - et al.
Selective inhibitors of fatty acid amide hydrolase relative to neuropathy target esterase and acetylcholinesterase: toxicological implications
Toxicol. Appl. Pharmacol.
(2002) - et al.
Effect of subchronic exposure to malathion on metabolic parameters in the rat
C. R. Biol.
(2007) - et al.
Evidence for the activation of organophosphate pesticides by cytochromes P450 3A4 and 2D6 in human liver microsomes
Toxicol. Lett.
(2000) - et al.
Toxicity of diazinon and its metabolites increases in diabetic rats
Toxicol. Lett.
(2007) - et al.
Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine-DTNB procedure
Toxicol. Appl. Pharmacol.
(1970)