Comparative effects of dimethylsulfoxide on metabolism and toxicity of carbon tetrachloride and dichloromethane.
The effects of dimethylsulfoxide (DMSO) on the metabolism and toxicity of chlorinated methanes were examined. Male mice were treated with DMSO (1, 2.5 or 5 ml kg(-1), i.p.) prior to challenge with dichloromethane (CH(2)Cl(2)) or carbon tetrachloride (CCl(4)). Blood carboxyhemoglobin elevation resulting from metabolic conversion of CH(2)Cl(2) to carbon monoxide was inhibited dose-dependently by DMSO pretreatment. The elevation of serum aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase activities induced by CCl(4) (0.1 mmol kg(-1)) was not changed in mice pretreated with DMSO at 1 ml kg(-1), but depressed significantly at a greater dose of DMSO. However, DMSO failed to alter the hepatotoxicity of CCl(4) injected at a dose of 0.2 mmol kg(-1). DMSO induced the microsomal p-nitrophenol hydroxylase and p-nitroanisole O-demethylase activities as early as 2 h following the treatment. Microsomal disposition of CH(2)Cl(2) and CCl(4) was measured using a vial equilibration technique. The disappearance of CH(2)Cl(2) was inhibited competitively by addition of DMSO. But DMSO did not affect the metabolic degradation of CCl(4). The results indicate that DMSO has multiple effects on metabolism and toxicity of xenobiotics. DMSO induces the hepatic metabolizing activity mediated by CYP2E1, but the presence of this solvent in the enzyme site may inhibit directly the enzymatic interaction with a substrate. The toxicological significance of DMSO-induced effects on such an interaction may be variable depending on the properties of each substrate. The invulnerability of CCl(4) metabolism to the effects of DMSO appears to be related to its high affinity for the lipophilic CYP enzyme site.
Kim
Sun J
SJ
College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul, Korea.
Jung
Young S
YS
Yoon
Mi Y
MY
Kim
Young C
YC
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D002251:Carbon Tetrachloride / Q000378:metabolism* / Q000633:toxicity*; D002263:Carboxyhemoglobin / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D000860:Hypoxia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D007700:Kinetics; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism; D008297:Male; D008752:Methylene Chloride / Q000378:metabolism* / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010090:Oxidoreductases, O-Demethylating / Q000096:biosynthesis; D012997:Solvents / Q000494:pharmacology*; D013997:Time Factors
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D012997:Solvents; D008752:Methylene Chloride; D002263:Carboxyhemoglobin; D002251:Carbon Tetrachloride; C026048:4-nitroanisole O-demethylase; D010090:Oxidoreductases, O-Demethylating; D007064:L-Iditol 2-Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D004121:Dimethyl Sulfoxide