We studied the effects of the neurotoxin, 6-hydroxydopamine (6-OHDA), on cultured fat-storing cells (FSCs) and hepatocytes. If either FSCs or hepatocytes were exposed to 6-OHDA for 4 hr, the neurotoxicant induced cell death in FSCs but not in hepatocytes. We decided to investigate why hepatocytes were refractile to injury from 6-OHDA while FSCs were labile. The activity of antioxidant enzymes within FSCs grown in vitro is remarkably lower than the activity in hepatocytes. Indeed, some specific antioxidant enzymes in FSCs were undetectable by our assays, but were easily detected in hepatocytes. Furthermore, the profile of antioxidant activity in FSCs was found to be almost identical to the profiles seen in cultured fibroblasts or myocytes. However, indirect immunolocalization of tyrosine hydroxylase in FSCs using anti-tyrosine hydroxylase antibodies was negative. Mazindol, a dopaminergic receptor antagonist, did not alleviate the toxicity of 6-OHDA suggesting that FSCs do not appear to possess a dopaminergic receptor. When the cell morphology of FSCs was examined by an indirect immunofluorescence technique, treatment of FSCs with 6-OHDA at a concentration of 200 microM for 2 hr modified the organization of alpha-smooth muscle actin into an irregular punctate pattern. Indeed, we found that the effects of 6-OHDA on cytoskeletal alterations and on the cell viability of FSCs were irreversible. These data suggest that : (1) 6-OHDA can cause irreparable injury to FSCs, but not hepatocytes; (2) hepatocytes are specially adapted to withstand an oxidative attack in contrast to FSCs. fibroblast and myocytes; (3) FSCs resemble other somatic cells in their low levels of antioxidant enzymes; and (4) this low profile of antioxidant activity may be responsible for the cell death and cytoskeletal alterations observed in FSCs in response to 6-OHDA.