ToxSci Advance Access originally published online on June 12, 2003
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Toxicological Sciences 75, 16-24 (2003)
Copyright © 2003 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Prolonged Ethanol Ingestion Enhances Benzene Myelotoxicity and Lowers Urinary Concentrations of Benzene Metabolite Levels in CD-1 Male Mice
* Research Centre, Toxicology Division, Department of Internal Medicine, University of Pavia, Pavia, Italy, and
Research Centre, Toxicology Division, Salvatore Maugeri Foundation IRCCS, Institute of Pavia, Pavia, Italy
Benzene toxicity is attributed to its metabolism, which is primarily mediated by the ethanol-inducible cytochrome P450 2E1 isoform (CYP2E1). The present study investigated the myelotoxicity and urinary concentrations of major benzene metabolites in adult CD-1 male mice treated with low levels of benzene vapors, ethanol, or a combination of the two. Groups of ethanol-treated (5% in a Lieber-DeCarli liquid diet, 3 weeks) or pair-fed control mice were exposed to 10 ppm benzene, 6 h per day, 5 days per week for 2 weeks, starting from the second week of ethanol administration. On the last day of treatment, the number of early and late erythroid progenitors (BFU-E and CFU-E) was reduced by 55%, while the number of granulocyte/macrophage progenitors (CFU-GM) was reduced by 36% in benzene-treated mice. Ethanol lowered the CFU-E, BFU-E, and CFU-GM colony formation by 33, 28, and 12%, respectively. In animals coexposed to benzene and ethanol, the CFU-E colony counts were decreased by 70%, the BFU-E by 80%, and the CFU-GM by 45%. Phenol (Ph), hydroquinone (HQ), catechol (Cat), and trans,trans-muconic acid (MA) were measured by HPLC-UV in urine samples collected weekly during the last 6-h benzene/air exposure session. In benzene-exposed mice urinary metabolite levels peaked at the end of the first week of treatment (µg/kg body weight (bw): Ph: 4931 ± 1055; Cat: 109 ± 17; HQ: 784 ± 137; MA: 534 ± 92) and significantly decreased at the end of the second week (µg/kg bw: Ph: 3909 ± 984; Cat: 82 ± 24; HQ: 337 ± 72; MA: 235 ± 55). In mice given benzene and ethanol, the urinary levels of Ph, Cat, HQ, and MA were significantly lower than those measured in the group given benzene alone. The urinary levels of Ph and Cat showed a decreasing trend, again, from the first to the second week of benzene exposure. These data indicate that chronic ethanol ingestion exacerbates benzene myelotoxicity and, in addition, reduces the urinary excretion of benzene metabolites in mice, suggesting that the influence of ethanol intake should be considered carefully in biomonitoring benzene exposure.
Key Words: ethanol; benzene; metabolism; bone marrow; phenol; catechol; hydroquinone; muconic acid.