Dose-dependent kinetics and metabolism of 1,2-dichlorobenzene in rat: effect of pretreatment with phenobarbital.
1. Toxicity of halobenzenes has been ascribed mainly to their epoxides, but recent studies with bromobenzene have shown that secondary quinone metabolites are also involved in the alkylation of hepatic proteins. However, the relative contribution of the quinones and the epoxides to the toxicity of halobenzenes is still unclear. In order to investigate the relation between metabolism and toxicity of 1,2-dichlorobenzene (1,2-DCB), the biotransformation, tissue distribution, blood kinetics, and excretion at three different oral dose levels (5, 50 and 250 mg/kg) of the radiolabelled compound were investigated in the male Wistar rat. A toxic dose level (250 mg/kg, as demonstrated by Allis et al. 1992) was included. 2. The major route of elimination (75-85%) was renal excretion. Excretion via the faeces ranged from 19% for the low dose to 7% for the high-dose level. Excretion was nearly complete within 24 h for the low and mid-dose level, and within 48 h for the high-dose level. Pretreatment with phenobarbital resulted in a more rapid excretion for the high-dose level and an overall higher urinary excretion. Biliary excretion was 50-60%, indicating a considerable enterohepatic circulation. 3. Highest concentrations of radioactivity after a low dose were found in fat, liver and kidney at 6 h after administration, and then declined rapidly. 4. The maximum concentration of radioactivity in blood was reached at 6-8 h for the low and mid-dose level, and at 24 h for the high-dose level. The concentration of parent chemical was essentially constant during 3 and 6 h for the mid- and high-dose level respectively, and then declined. 1,2-DCB could only be detected in blood in the first 2 h after administration of the 5-mg/kg dose. 5. The major route of biotransformation was via the glutathione pathway and 60% of the urinary metabolites were mercapturic acids. In addition, the major metabolites in bile were conjugates of glutathione. Other major metabolites in urine were the sulphate conjugates of 2,3- and 3,4-dichlorophenol (DCP). No significant differences in metabolic profiles were observed between the different doses. Induction with phenobarbital resulted in the increased excretion of sulphate conjugates (30% in the induced rat, 20% in the control rat), mainly the conjugate of 3,4-DCP. 6. The mercapturic acids in urine and glutathione conjugates in bile were epoxide-derived, whereas no quinone- or hydroquinone-derived metabolites were observed. Therefore the hepatotoxicity of 1,2-dichlorobenzene is assumed to be related, at least partly, to the presence of the intermediate arene oxide. A high dose of 1,2-DCB will result in depletion of GSH, followed by oxidative stress and possible binding to macromolecules.
Hissink
A M
AM
Division of Toxicology, TNO Nutrition and Food Research Institute, Zeist, Netherlands.
Van Ommen
B
B
Van Bladeren
P J
PJ
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001711:Biotransformation; D002722:Chlorobenzenes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006868:Hydrolysis; D007306:Insecticides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D002722:Chlorobenzenes; D007306:Insecticides; C004726:2-dichlorobenzene; D010634:Phenobarbital