Influence of hyperthyroidism on lindane-induced hepatotoxicity in the rat.
Parameters related to hepatic oxidative stress, cell injury, phagocytic activity, and liver histology were studied in control rats and in animals subjected to L-3,3',5-triiodothyronine (T3) and/or lindane administration. Hyperthyroidism elicited a calorigenic response and increased rates of hepatic O2 uptake, which were not modified by lindane treatment. T3 diminished serum lindane levels as well as those in the liver and adipose tissue, whereas lindane enhanced serum T3 levels in animals given T3. Compared with control rats, lindane significantly increased the rate of formation of thiobarbituric acid reactants (TBARS) by the liver, with no changes in either the reduced glutathione (GSH) content, the TBARS/GSH ratio as indicator of oxidative stress, or in the fractional rates of lactate dehydrogenase (LDH) and GSH efflux from perfused livers as integrity parameters. Hyperthyroidism induced GSH depletion in the liver, with a significant enhancement in the TBARS formation, the TBARS/GSH ratio, and in the fractional LDH and GSH efflux. These parameters were increased further by joint T3 and lindane administration in a magnitude exceeding the sum of the effects produced by the separate treatments. In addition, hyperthyroidism led to Kupffer cell hyperplasia and significant increases in serum glutamate oxalacetate transaminase (GOT) and in hepatic zymosan-induced chemiluminescence, while liver myeloperoxidase (MPO) activity was found unchanged, compared with controls. Rats treated with lindane presented normal liver histology, with no changes in biochemical parameters related to cell injury. The joint administration of T3 and lindane, however, elicited a marked elevation in serum GOT and glutamate pyruvate transaminase (GPT), concomitantly with extensive liver necrosis and the presence of granulomas containing lymphocytes, Kupffer cells and polymorphonuclear leukocytes (PMN). In this condition, hepatic zymosan-induced light emission and MPO activity were enhanced over control values. It is concluded that hyperthyroidism increases the susceptibility of the liver to the toxic effects of lindane, which seems to be accomplished by potentiation of the hepatic oxidative stress status. The latter effect may be conditioned by an enhanced phagocytic respiratory burst activity due to the observed Kupffer cell hyperplasia and PMN infiltration, in addition to the increased production of reactive oxygen species in parenchymal cells.
Videla
L A
LA
Departamento de Bioqímica, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Smok
G
G
Troncoso
P
P
Simon
K A
KA
Junqueira
V B
VB
Fernández
V
V
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D005978:Glutathione / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D006980:Hyperthyroidism / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008163:Luminescent Measurements; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008853:Microscopy; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014284:Triiodothyronine / Q000097:blood / Q000633:toxicity; D015054:Zymosan / Q000494:pharmacology
D014284:Triiodothyronine; D001556:Hexachlorocyclohexane; D015054:Zymosan; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione