Phase II metabolism of benzene.
The hepatic metabolism of benzene is thought to be a prerequisite for its bony marrow toxicity. However, the complete pattern of benzene metabolites formed in the liver and their role in bone marrow toxicity are not fully understood. Therefore, benzene metabolism was studied in isolated rodent hepatocytes. Rat hepatocytes released benzene-1,2-dihydrodiol, hydroquinone (HQ), catechol (CT), phenol (PH), trans-trans-muconic acid, and a number of phase II metabolites such as PH sulfate and PH glucuronide. Pretreatment of animals with 3-methylcholantrene (3-MC) markedly increased PH glucuronide formation while PH sulfate formation was decreased. Likewise, V79 cells transfected with the 3-MC-inducible rat UGT1.6 cDNA showed a considerable rate of PH and HQ glucuronidation. In addition to inducing glucuronidation of phenols, 3-MC treatment (reported to protect rats from the myelotoxicity of benzene) resulted in a decrease of hepatic CYP2E1. In contrast, pretreatment of rats with the CYP2E1-inducer isopropanol strongly enhanced benzene metabolism and the formation of phenolic metabolites. Mouse hepatocytes formed much higher amounts of HQ than rat hepatocytes and considerable amounts of 1,2,4-trihydroxybenzene (THB) sulfate and HQ sulfate. In conclusion, the protective effect of 3-MC in rats is probably due to a shift from the labile PH sulfate to the more stable PH glucuronide, and to a decrease in hepatic CYP2E1. The higher susceptibility of mice toward benzene may be related to the high rate of formation of the myelotoxic metabolite HQ and the semistable phase II metabolites HQ sulfate and THB sulfate.
Schrenk
D
D
Institute of Toxicology, University of Tübingen, Germany. dieter.schrenk@unituebingen.de
Orzechowski
A
A
Schwarz
L R
LR
Snyder
R
R
Burchell
B
B
Ingelman-Sundberg
M
M
Bock
K W
KW
D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013431:Sulfates / Q000378:metabolism
D005965:Glucuronates; D013431:Sulfates; D008748:Methylcholanthrene; D019392:Cytochrome P-450 CYP2E1; D001554:Benzene