Kinetics and metabolism of 1,4-dichlorobenzene in male Wistar rats: no evidence for quinone metabolites.
The biotransformation and kinetics of 1,4-dichlorobenzene (1,4-DCB) were studied in male Wistar rats at three oral dose levels (10, 50 and 250 mg/kg). The effect of induction of CYP2E1 by isoniazid on the kinetics and biotransformation was determined. Excretion was predominantly via the urine (78-85%) and to a small extent via the faeces (2-5%). The relative contributions of these routes were not dose dependent. Excretion via the bile ranged from less than 5% at the low dose level to 30% at the high dose level. The major biliary metabolite was the glucuronide of 2,5-dichlorophenol (2,5-DCP). The time point at which the plasma concentrations of the parent compound and the metabolites were maximal (TCmax) as well as the maximum concentrations (Cmax) increased with higher dose level. Induction by isoniazid resulted in a faster urinary elimination, whereas TCmax and Cmax were lower for induced rats. In addition, the area under the blood curve (AUC) was smaller and total clearance was higher for induced rats. 1,4-DCB was mainly metabolized to 2,5-DCP (ca. 90%), which was detected in the urine as its sulfate (50-60%), glucuronide (20-30%) and the free form (5-10%). Minor metabolites were the N-acetyl-cysteine-S-dihydro-hydroxy-1,4-dichlorobenzene and the corresponding dehydrated N-acetyl-cysteine-S-1,4-dichlorobenzene, which comprised ca. 10% of total metabolites. No hydroquinones were observed for the male Wistar rat, not even under conditions of induced oxidative metabolism.
Hissink
A M
AM
TNO Nutrition and Food Research Institute, Toxicology Division, Zeist, The Netherlands. hissink@voeding.tno.nl
Dunnewijk
R
R
van Ommen
B
B
van Bladeren
P J
PJ
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D016227:Benzoquinones / Q000378:metabolism*; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002722:Chlorobenzenes / Q000097:blood / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000096:biosynthesis; D004790:Enzyme Induction; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D016227:Benzoquinones; D002273:Carcinogens; D002722:Chlorobenzenes; C004532:quinone; C018511:4-dichlorobenzene; D019392:Cytochrome P-450 CYP2E1