ML236B in lipid-depleted serum (6). We therefore assayed HMG-Co A reductase activity in the MF-2 clone by exposing it to ML236B for longer periods than previously reported (6). As a function of exposure time, the cellular contents of HMG-Co A reductase increased 30-fold (1 week) and 53-fold (4 weeks) in comparison to the values found for MF-2 cells (Table 1). Exposure of V79 cells to 2µg/ml ML236B produced a cytotoxic effect after incubation for more than 2 days (data not shown). We then examined whether the crystalloid, smooth endoplasmic reticulum structure observed by Chin et al.(1) is present when an ML236B-resistant clone is exposed to the drug. No significant difference was found in the structures of cellular organelles of V79 and MF-2 (data not shown, also see Fig. 1A). By contrast, M L236B-treated MF-2 cells showed marked changes in morphology. MF-2 cells grown in the presence of 2µg/ml ML236B for 1 week in lipid-depleted medium, numerous enlarged vacuoles or an enlarged rough endoplasmic reticulum (empty) were observed (Fig. 1B). In almost all the MF-2 cells grown in the presence of 2 µg/ml ML236B for 4 weeks in lipid-depleted medium, three major morphological changes were seen. In the cisternae of the rough endoplasmic reticulum were greatly distended and frequently contained flocculated substances (Fig. 1D). The outer nuclear membrane was ballooned out in many areas, producing distension of the perinuclear space (Fig. 1C). Three apparent ultrastructural changes were noted in the thin sections of MF-2 cells grown in ML236B: dilated cisternae of the rough endoplasmic reticulum that contained or did not contain flocculated contents; significant distension of the perinuclear and vesicular inclusion bodies in the nuclei. Although our ML236B-resistant mutants derived from V79 cells also induced a high concentration of reductase (Table 1), we found none of the crystalloid, smooth