Responses to zinc, applied in concentrations ranging from 3 to 200 microM Zn2+, were investigated in rat hepatoma tissue culture (HTC) cells and in primary cultured rat hepatocytes. The uptake of 65Zn, total Zn levels, cellular viability, metallothionein (MT) levels, superoxide dismutase (SOD) activities, and glutathione (GSH) levels were measured. Exposure at 50-200 microM Zn for 24 hr resulted in up to fivefold increases in intracellular Zn accumulation in hepatocytes and up to twofold increases in rat HTC cells. Hepatocytes increased their MT levels from 80 to 230 pmol MT/mg cell protein, whereas MT levels in HTC cells did not significantly change with increasing Zn applications. SOD activities rapidly increased in both cell types for applied [Zn] > 25 microM, eventually reaching up to two to three times the control SOD values at 200 microM applied Zn concentrations. GSH levels in hepatocytes increased to twice the control values, but gradually declined again with applied Zn concentrations > 100 microM, the latter probably due to progressive increases in GSH efflux. Cell viability tests indicated differences between effects on cellular metabolism (ATP levels) and effects on cellular condition (LDH leakage, 42K influx). The ATP data suggest significant but comparable Zn effects on cellular metabolism in both cell types, notwithstanding the large differences in cellular Zn, MT, and GSH levels. At comparable cytosolic total Zn levels, hepatocytes appeared more effectively protected against intracellular Zn toxicity by elevated MT and GSH levels. However, if considered with respect to applied Zn concentrations, at 200 microM cellular viability (LDH leakage) was more affected in hepatocytes than in HTC cells, the latter probably due to progressive sequestering of zinc on intracellular Zn-complexing compounds (MT, GSH) and subsequent accumulation of zinc in hepatocytes, in contrast with the absence of excessive Zn uptake by HTC cells. The overall results indicate that synthesis of (protective) cellular compounds like MT or GSH, although rendering cells resistant to metals, may--at the same time--result in relatively strong accumulation of potentially toxic metals.