QUANTITATION OF ALPHA(2)-MICROGLOBULIN AFTER ADMINISTRATION OF STRUCTURALLY DIVERGENT CHEMICAL-COMPOUNDS

alpha(2)-Microglobulin-induced nephropathy is a phenomenon which is ex clusively found in adult male rats. Various chemicals are able to bind to alpha(2)-microglobulin thus inhibiting its proteolytic degradation in lysosomes of the P2 segment of the rat nephron. The accumulation o f this protein in 'protein droplets' or 'hyaline droplets' leads to ne crosis, followed by regeneration which possibly later results in the f ormation of tumours, Here we report the development of a monoclonal an tibody which is specific for alpha(2)-microglobulin. It was utilized t o measure alpha(2)-microglobulin concentrations in plasma and tissues, and to stain alpha(2)-microglobulin in fixed tissue slides. In two st udies we administered to adult male Wistar rats two groups of compound s: (1) one group of structurally diverse compounds, which give an over view of chemical entities capable of inducing the accumulation of alph a(2)-microglobulin; and (2) another group of structurally closely rela ted compounds (i.e. substituted benzene derivatives) for the purpose o f elucidating possible structure-activity relationships. The degree of alpha(2)-microglobulin-induced nephropathy was determined by immunohi stochemical staining of kidney sections. In addition, liver and kidney tissue and plasma concentrations of alpha(2)-microglobulin were measu red by competitive ELISA. Liver tissue and plasma concentrations of al pha(2)-microglobulin were not found to be elevated whereas kidney tiss ue concentrations were higher than the controls. The increase over con trol values ranged from 154% (1,4-dichloromethyl-benzene) to 321% pha- methyl-4-(1-methylethyl)-cyclohexanemethanol]. Comparing structurally related benzene derivatives, the hyaline droplet accumulating (HDA) po tential was found to depend both on the type of substituent and its po sition at the aromatic ring. III general HDA activity increased in the order benzene congruent to phenol congruent to alkylated phenols < ha logenated phenols < halogenated benzenes. Further QSAR studies are nee ded to provide a theoretical base for these observations.