Biochemical mechanisms and pathobiology of alpha 2u-globulin nephropathy

alpha 2u-N is a syndrome that has been characterized in male rats exposed to a number of environmental chemicals and pharmacological agents. The chemicals or their metabolites bind to alpha 2u, which is believed to lead to a less digestible chemical-protein complex. Because of the decreased hydrolysis of the chemical-protein complex in the lysosome, alpha 2u accumulates in the form of protein droplets. In extensive nephropathy, the accumulation of alpha 2u in the lysosome results in polyangular crystalloid droplets that lead to lysosomal overload and eventually cell death. This cell death stimulates restorative cell replication which promotes renal carcinogenesis in male rats. As such, it is imperative that extrapolation of risk to humans of chemicals causing this syndrome be performed. Because the nongenotoxic mechanism for carcinogenesis in the male rat involves a unique protein, such extrapolations can only be done incorporating species differences in the critical factors that result in alpha 2u-N in rats. Presently, these data suggest a markedly reduced risk for humans compared to male rats.