Inhibition of Ethoxyacetic Acid (EAA) Production From Ethylene Glycol Monoethyl Ether (EGE) Upon Combined Administration with Toluene (TOL) and Xylene (XYL) in Male Rats

초록

Upon mixed administration of EGE (200 mg/kg), TOL (250 mg/kg) and XYL (500 mg/kg) to male rats, the Cmax and AUC of EAA were decreased by 51% and 28%, respectively. This explained the diminished testicular atrophy observed by Yu et al (1997). In rats pretreated with acetone (AC), in which the hepatic microsomal CYP2E1 activity responsible for the initial oxidation of TOL and XYL was increased, the Cmax and AUC of hippuric acid (HA) and methylhipuric acid (MHA), the final metabolites of TOL and XYL, were increased by 2 to 3 folds. However, when EGE was given to these rats, in contrast to expectation, the Cmax and AUC of EAA were not decreased. Futhermore, when the EGE mixed with TOL and XYL was given to these rats, to our surprise, the Cmax and AUC of EAA were increased by 31% and 39%, respectively. This indicated that the EGE derived testicular atrophy may occur with greater severity in rats with increased CYP2E1 activity and predicted that alcohol drinking workers employed in paint industry exposed to mixed solvents are at greater risk for reproductive toxicity. In rats pretreated with 3-methylcholanthrene (MC), in which the CYP1A2 activity also responsible for initial oxidation of TOL and XYL was increased, the Cmax and AUC of both the HA and MHA were increased as expected. When EGE was given to these rats, the Cmax and AUC of EAA were decreased by 32% and 42%, respectively. This indicated that rats with increased CYP1A2 activity are not as susceptible as the control rats for the EGE derived testicular toxicity. However, when EGE mixed with TOL and XYL is given to these rats, quite unexpectedly, the plasma concentration of EAA was maintained at high level for 12 hr and the Cmax and AUC values were increased by 39% and 74%, respectively. This indicated that rats with increased CYP1A2 activity are much more susceptible to the EGE derived testicular atrophy when they are given EGE in combination with TOL and XYL containing solvent mixture and predicted that cigarette