J. Temmink, I. Bruggeman, P. J. Bladeren
Jul 1, 1986
Citations
0
Influential Citations
11
Citations
Quality indicators
Journal
Archives of Toxicology
Abstract
Since allyl isothiocyanate has been reported to be a bladder carcinogen and benzyl isothiocyanate is a known anti-carcinogen, it is important to know the mode of their cytotoxic action. This was investigated in a RL-4 hepatocyte cell line by studying the morphological effects of increasing concentrations of the isothiocyanates and their glutathione and cysteine conjugates. These effects were compared with those induced by tert-butylhydroperoxide which supposedly has its primary effect upon the cytosolic glutathione status and thus upon the integrity of Ca2+-sequestrating mitochondria.The results agree with the previously postulated role of conjugation in the exposure of cells to isothiocyanates: Conjugates show effects similar to those produced by the free parent compounds because conjugates release free isothiocyanates in aqueous solution. The cytomorphological effects increase in a more or less dose-dependent manner with increasing concentrations of isothiocyanate or exposure time. Probably due to increased exposure, suspended RL-4 cells are more sensitive to the toxic action than cells growing on a substrate. No qualitative differences were found between the effects of allyl and benzyl isothiocyanate, indicating that their different effects in vivo are perhaps related to organ-specific differences in equilibrium between the conjugated and unconjugated forms of the test substances. The first cytomorphological effects of isothiocyanates consist of surface blebbing (zeiosis) and swelling of dictyosomal cisternae. At higher concentrations swelling extends to vesicles of endoplasmic reticulum. Mitochondria are not affected until the cells reach the necrotic phase of injury. In contrast, tert-butylhydroperoxide causes mitochondrial damage in an early pase of toxic injury. The cellular symptoms suggest that the primary target of isothiocyanates is in the plasma membrane and the cellular membrane system, affecting the monovalent cation and water balance of the cell organelles rather than the Ca2+ homeostasis as in cells exposed to tert-butylhydroperoxide. Differences in lipophilicity may be at the basis of this differenc in primary action.