INTRACELLULAR CALCIUM-CONCENTRATION IMPAIRMENT IN HEPATOCYTES FROM THIOACETAMIDE-TREATED RATS - IMPLICATIONS FOR THE ACTIVITY OF CA2-DEPENDENT ENZYMES()

Methods/Results: Thioacetamide induced a severe perivenous necrosis fo llowed by a hepatocellular regenerative response, when administered in a single dose of 6.6 mmol/kg to rats, As (Ca2+)(i) plays an important role in both toxic cell killing and cell proliferation, the disturban ces in the basal cytosolic calcium as well as the levels of Ca2+ seque stered in the endoplasmic reticulum were determined in hepatocytes iso lated at 0, 12, 24, 48 and 72 h after thioacetamide administration. Th e basal Ca2+ increased progressively, reaching a maximum at 24 h of th e intoxication (205%, p<0.001), while the microsomal sequestered Ca2decreased at 24 h to 16% (p<0.001) when compared with untreated contro ls, Changes in the activity of glycogen phosphorylase a paralleled tho se of basal free calcium and showed the maximum value also at 24 h (29 1%; p<0.001). Moreover, there was a close association in time between the basal concentration of Ca2+ and the inhibition of microsomal Ca2+- dependent ATPase activity. Conclusions: The significant decrease in th e levels of GSH and protein thiols indicates that oxidative stress is involved in thioacetamide-induced cell injury, but these decreases did not precede changes in cytosolic Ca2+ level, In the sequence of event s leading to hepatic cell injury and regeneration, thioacetamide mobil ized hepatic (Ca2+)(i) via inhibition of microsomal Ca2+-ATPase which may have activated Ca2+-dependent mechanisms involved both in cell dea th and in acute mitogen response.