INFLUENCE OF AROMATIC-HYDROCARBONS ON THE METABOLISM OF DICHLOROMETHANE TO CARBON-MONOXIDE IN RATS

The influence of prior or simultaneous oral administration of benzene, toluene, o-, m-, or p-xylene on the carboxyhemoglobin (COHb) level after a single dose of dichloromethane (DCM) was investigated in male rats. Six hours after administration of DCM, 6.2 mmol/kg, the mean maximum COHb level was 9.3 +/- 1.9%. This level was significantly enhanced by prior administration of benzene (16.9 mmol/kg) at 12-24 h, of toluene (18.8 mmol/kg) at 20-28 h, of o- (16.6 mmol/kg) and m-xylene (16.3 mmol/kg) at 20-32 h, and of p-xylene (16.2 mmol/kg) at 24-32 h. The corresponding maximum COHb levels were 20.7 +/- 1.3, 18.6 +/- 1.1, 18.9 +/- 1.1, 22.7 +/- 1.2. and 13.2 +/- 1.0%, respectively. After simultaneous administration of both DCM and the aromatic solvent, the COHb formation was inhibited: values of 1.3 +/- 0.3, 1.7 +/- 0.4, 3.6 +/- 0.2, 1.9 +/- 0.2, and 2.0 +/- 0.2% COHb, respectively, were found. The inhibition was also evident when DCM was administered 12 h after toluene or m-xylene and 12, 16 or 20 h after p-xylene. The inhibition was dose-related as seen after combined gavage of o-, m-, or p-xylene and DCM. The o- and m-, but not the p-methylhippuric acid (MHA) excretion in the urine was significantly reduced after simultaneous administration of equimolar doses of DCM and the corresponding xylenes. In conclusion, it seems that the stimulation or inhibition of the COHb formation after DCM caused by pretreatment with or by simultaneous administration of the aromatic solvents is due to the induction of cytochrome P450 IIE1 or to competition between DCM and the aromatic solvent on this isozyme of cytochrome P450.