Biochemical effects of three carcinogenic chlorinated methanes in rat liver.
Three chlorinated methanes, carbon tetrachloride, chloroform, and methylene chloride, known to cause liver tumors in rodents, were given by oral gavage to adult female rats both 21 h and 4 h before sacrifice. Then hepatic DNA damage, ornithine decarboxylase (ODC), cytochrome P-450, glutathione content, and serum alanine aminotransferase (SGPT) activity assays were performed. Carbon tetrachloride increased rat hepatic ODC activity and decreased cytochrome P-450 content at doses both below and above cytotoxicity (as measured by increased SGPT activity). At 54 and 160 mg/kg, chloroform increased hepatic ODC activity with minimal or no elevation in SGPT activity. At 480 mg/kg chloroform increased hepatic ODC and SGPT activity. A dose of 1,275 mg/kg methylene chloride caused a small, but significant amount of hepatic DNA damage. When these three compounds are compared on either an equimolar or equitoxic (1/5 LD50) basis, their ability to induce hepatic ODC or increase SGPT activity was carbon tetrachloride greater than chloroform greater than methylene chloride. The results of this biochemical study are interpreted with respect to the ability of chemicals to cause hepatic cancer by either genetic or epigenetic mechanisms.
Kitchin
K T
KT
Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27211.
Brown
J L
JL
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D015197:Carcinogenicity Tests; D002273:Carcinogens; D002725:Chloroform / Q000008:administration & dosage / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000008:administration & dosage / Q000633:toxicity*; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008752:Methylene Chloride / Q000008:administration & dosage / Q000633:toxicity; D009955:Ornithine Decarboxylase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D006843:Hydrocarbons, Chlorinated; D008752:Methylene Chloride; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D009955:Ornithine Decarboxylase; D005978:Glutathione