Differential inhibitory effects of carbon tetrachloride on the hepatic plasma membrane, mitochondrial and endoplasmic reticular calcium transport systems: implications to hepatotoxicity.
Mitochondrial, endoplasmic reticular and plasma membrane fractions were isolated by a new method from control male Fischer 344 rats and rats given CCl4 by gavage. After 1 h of CCl4 treatment, rats were in glucose and pancreatic hormone balance but plasma levels of T3 and T4 were decreased 29 and 22%, respectively. After 24 hours of CCl4 treatment, rats were: hypoglycaemic and insulin and glucagon levels were increased 33- and 35-fold, respectively; total T4 levels were decreased 62%; while total T3 levels were normalized. In liver fractions from CCl4-treated rats, 1 h after CCl4 administration: (i) calcium binding was decreased 65% in the mitochondrial fraction, 66% in the endoplasmic reticular fraction and 46% in the plasma membrane fraction; (ii) calcium uptake was decreased 59% in the mitochondrial fraction, 46% in the endoplasmic reticular fraction and 37% in the plasma membrane fraction. After 24 h of CCl4 administration: (i) calcium binding was decreased 57% in the mitochondrial fraction, 50% in the endoplasmic reticular fraction and 71% in the plasma membrane fraction; (ii). calcium uptake was decreased 55% in the mitochondrial fraction, 17% in the endoplasmic reticular fraction and 53% in the plasma membrane fraction. In vitro studies indicated the plasma membrane calcium transport system to be rapidly (within a minute) and strongly (>90%) inhibited by CCl4. We conclude that CCl4 produces a differential inhibitory effect on the hepatocyte calcium pumps that are implicated with hepatocellular damage.
Hemmings
Susan J
SJ
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. hemmings@sask.usask.ca
Pulga
Vivian B
VB
Tran
Sam T
ST
Uwiera
Richard R E
RR
D000818:Animals; D001693:Biological Transport, Active; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005934:Glucagon / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced; D007328:Insulin / Q000097:blood; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood
D001786:Blood Glucose; D002121:Calcium Channel Blockers; D007328:Insulin; D014284:Triiodothyronine; D005934:Glucagon; D002251:Carbon Tetrachloride; D013974:Thyroxine; D002118:Calcium