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ToxSci Advance Access published online on June 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg163
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 10, 2003; accepted May 27, 2003
© 2003 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

Giorgio Marrubini 1*, Anna F. Castoldi 2, Teresa Coccini 2, and Luigi Manzo 3

1 Research Centre, Toxicology Division, Department of Internal Medicine, University of Pavia, Pavia, Italy
2 Research Centre, Toxicology Division, Salvatore Maugeri Foundation IRCCS, Institute of Pavia, Pavia, Italy
3 Research Centre, Toxicology Division, Department of Internal Medicine, University of Pavia, Pavia, Italy; Research Centre, Toxicology Division, Salvatore Maugeri Foundation IRCCS, Institute of Pavia, Pavia, Italy

* To whom correspondence should be addressed. E-mail: gmarrubini{at}fsm.it.


  Abstract

Benzene toxicity is attributed to its metabolism which is primarily mediated by the ethanol-inducible cytochrome P450 2E1 isoform (CYP 2E1). The present study investigated myelotoxicity and urinary concentrations of major benzene metabolites in adult CD-1 male mice treated with low levels of benzene vapours, ethanol or their combination.

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/day, 5 days/wk for 2 weeks starting from the second week of ethanol administration. On the last day of treatment the number of hematopoietic progenitors, early and late erythroid progenitors (BFU-E and CFU-E) was reduced by 55%, while that of granulocyte/macrophage progenitors (CFU-GM) by 36% in benzene-treated mice. Ethanol lowered CFU-E, BFU-E and CFU-GM colony formation by 33%, 28% and 12%, respectively. In animals coexposed to benzene and ethanol CFU-E colony counts were decreased by 70%, BFU-E by 80% and 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 6h-benzene/air exposure session. In benzene-exposed mice urinary metabolite levels peaked at the end of the first week of treatment (µg/kg 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 + ethanol urinary levels of Ph, Cat, HQ, and MA were significantly lower than those measured in the group given benzene alone. Urinary levels of Ph and Cat, again, showed a decreasing trend from the first to the second week of benzene exposure. Altogether, these data indicate that chronic ethanol ingestion exacerbates benzene myelotoxicity and, in addition, reduces the urinary excretion of benzene metabolites in mice, suggesting that influence of ethanol intake should be carefully considered in biomonitoring benzene exposure.

Key Words: ethanol, benzene, metabolism, bone marrow, phenol, catechol, hydroquinone, muconic acid .


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