Effect of a single administration of benzene, toluene or m-xylene on carboxyhaemoglobin elevation and metabolism of dichloromethane in rats.
The effect of a single administration of aromatic hydrocarbons (AHCs) on the metabolic activity responsible for the biotransformation of dichloromethane (DCM) to carbon monoxide (CO) was investigated using adult female rats. In rats treated orally with benzene (1.5 ml kg-1), toluene (2.0 ml kg-1) or m-xylene (2.0 ml kg-1) 16-24 h prior to DCM (3 mmol kg-1, i.p.), the carboxyhaemoglobin (COHb) level was elevated, reaching peaks in blood at 21%, 16% and 23%, respectively, compared to the peak of ca. 10% in rats treated with DCM only. Their effects on COHb generation were highly dependent on the time interval between each AHC and DCM treatment, since an early administration of m-xylene or toluene decreased the COHb elevation. The half-life of DCM in blood was shortened significantly, indicating that the metabolic degradation of DCM was enhanced by the AHCs. Disulfiram (3.4 mmol kg-1, p.o.) blocked COHb elevation completely, suggesting that the metabolic conversion of DCM to CO is mediated by cytochrome P-450 2E1 (P4502E1). Corresponding increases in the concentration and half-life of DCM in blood were also observed. A single administration of the AHCs did not alter the hepatic glutathione level, suggesting that the increase in DCM-induced COHb elevation was not due to hepatic glutathione depletion. In vitro studies showed that the hepatic microsomal metabolism of nitrosodimethylamine and p-nitrophenol was significantly increased by a single dose of each AHC. Total cytochrome P-450 content and p-nitroanisole demethylase activity were also increased; however, only toluene and m-xylene were effective inducers for aminopyrine N-demethylase. Therefore, benzene appears to be a selective inducer for P4502E1 compared to other alkylbenzenes. The results indicate that even a single dose of benzene, toluene or m-xylene may induce the activity of P4502E1 significantly, which is responsible for the increased generation of COHb from DCM, as demonstrated in the present study.
College of Pharmacy, Seoul National University, Korea.
S K
SK
Kim
Y C
YC
Kim
D000284:Administration, Oral; D000477:Alkylating Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001554:Benzene / Q000008:administration & dosage / Q000633:toxicity*; D002248:Carbon Monoxide / Q000378:metabolism; D002263:Carboxyhemoglobin / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D004128:Dimethylnitrosamine / Q000633:toxicity; D004221:Disulfiram / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008752:Methylene Chloride / Q000097:blood*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009596:Nitrophenols / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014050:Toluene / Q000008:administration & dosage / Q000633:toxicity*; D014992:Xylenes / Q000008:administration & dosage / Q000633:toxicity*
D000477:Alkylating Agents; D009596:Nitrophenols; D012997:Solvents; D014992:Xylenes; D014050:Toluene; D008752:Methylene Chloride; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; D001554:Benzene; D004128:Dimethylnitrosamine; C031285:3-xylene; D004221:Disulfiram; C024836:4-nitrophenol