Perturbations in polyamines and related enzymes following chlordecone-potentiated bromotrichloromethane hepatotoxicity.
The mechanism by which chlordecone (CD) amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. Recent work has shown that suppression of hepatocellular regeneration leads to accelerated progression of liver injury leading to complete hepatic failure due to an unusual interaction between individually nontoxic low-dose combination of CD and CCl4. Since polyamines are involved in cell division, their levels reflect the extent to which there is suppression of hepatocellular regeneration during CD and CCl4 interaction. The present studies were designed to investigate the polyamine levels and associated enzymes in livers of rats treated with BrCCl3 alone or CD and BrCCl3 low-dose combination in order to confirm whether the sequence of events of hepatotoxicity is similar to that seen in CCl4 toxicity or that seen during CD and CCl4 interaction. The extent of liver toxicity in rats fed 10 ppm chlordecone (CD) for 15 days prior to the injection of a single low dose of BrCCl3 (15 microL/kg body weight) or after exposure to a high dose of BrCCl3 (80 microL/kg body weight) without CD pretreatment, was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was also an increase in transaminase levels, in rats exposed to a single low dose of BrCCl3 alone (15 microL/kg body weight) but this increase was far below the high-dose exposure alone or the combination treatment. Hepatic levels of ornithine decarboxylase, S-adenosylmethionine decarboxylase, N1-acetylputrescine, N1-acetylspermidine, putrescine, spermidine, and spermine at the end of 24 hr increased after exposure to a low dose of BrCCl3 alone as compared to exposure to a high dose alone or the low-dose combination of CD and BrCCl3. Liver spermidine N1-acetyltransferase was elevated at 2, 6, and 24 hr after exposure to a high dose of BrCCl3 alone as compared to treatment with a low-dose combination of CD and BrCCl3 suggesting decreased synthesis of this enzyme, in spite of a greater need as seen from liver transaminase levels. In general, it was observed that there is significant elevation in some polyamines and related enzymes during toxicity of a low dose of BrCCl3 which seemed to stabilize within 24 hr. This was not observed with the other two groups of rats exposed either to BrCCl3 high dose alone or the low-dose combination of CD and BrCCl3.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
S B
SB
Rao
R A
RA
Young
H M
HM
Mehendale
D000123:Acetyltransferases / Q000378:metabolism; D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000599:Amino Acids, Diamino / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001975:Bromotrichloromethane / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D007631:Chlordecone / Q000633:toxicity*; D002725:Chloroform / Q000031:analogs & derivatives*; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D012437:Adenosylmethionine Decarboxylase; D000410:Alanine Transaminase; D000599:Amino Acids, Diamino; D001219:Aspartate Aminotransferases; D001975:Bromotrichloromethane; D007631:Chlordecone; D002725:Chloroform; D007306:Insecticides; D009955:Ornithine Decarboxylase; D011073:Polyamines; D011700:Putrescine; D000099228:Diamine N-Acetyltransferase; C000064:putreanine; C026212:N-acetylputrescine