title: Toxicity of diazinon and its metabolites increases in diabetic rats.
abstract: The effect of diazinon (DZN) on the activities of cholinesterase (ChE) in plasma and acetylcholinesterase (AChE) in erythrocyte and brain was investigated in normal and streptozotocin-induced diabetic rats. Hepatic drug-metabolizing enzyme activity was also estimated by measuring the systemic clearance of antipyrine, and the expression of hepatic cytochrome P450 (CYP) 3A2 and CYP1A2, which is closely related to the metabolism from DZN to DZN-oxon, a strong inhibitor of both ChE and AChE. No significant differences in the activities of ChE in plasma and AChE in erythrocyte were observed between normal and diabetic rats. Treatment with DZN significantly decreased these activities in diabetic rats more than in normal rats 6h after injection (6.5 mg/kg). Treatment with DZN significantly decreased the activity of AChE in brain of diabetic rats than normal rats 3h after injection (65 mg/kg), although no significant difference in the activity was found between normal and diabetic rats. The urinary recovery of diethylphosphate (DEP), a metabolite of DZN-oxon, was significantly increased in diabetic rats, but that of diethylthiophosphate (DETP), a metabolite of DZN, was unchanged. Significant increases in the systemic clearance of antipyrine and protein levels of hepatic CYP1A2, not CYP3A2, were observed in diabetic rats. These results suggest the possibility that a metabolite of DZN, DZN-oxon, causes higher toxicity in diabetic rats due to the enhancement of hepatic CYP1A2-mediated metabolism of DZN.
authors: Department of Medicinal Informatics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Jun
authors: J
authors: Ueyama
authors: Dong
authors: D
authors: Wang
authors: Takaaki
authors: T
authors: Kondo
authors: Isao
authors: I
authors: Saito
authors: Kenji
authors: K
authors: Takagi
authors: Kenzo
authors: K
authors: Takagi
authors: Michihiro
authors: M
authors: Kamijima
authors: Tamie
authors: T
authors: Nakajima
authors: Ken-Ichi
authors: K
authors: Miyamoto
authors: Shinya
authors: S
authors: Wakusawa
authors: Takaaki
authors: T
authors: Hasegawa
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003976:Diazinon / Q000493:pharmacokinetics / Q000633:toxicity*; D004912:Erythrocytes / Q000201:enzymology; D007306:Insecticides / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000110:Acetylcholinesterase; D002802:Cholinesterases; D003976:Diazinon