Primary cultures of cells derived from the rat proximal tubule were exposed to up to 200 µM λ- or χ-light chain obtained from myeloma patients. Light chains inhibited the uptake of both phosphate and glucose by the cells while albumin had no effect. The half-maximal inhibitory concentration (IC50) of both the λ-and ĸ-light chains on phosphate transport were similar, 34 and 35 µM respectively. The IC50 of the ĸ-light chain on glucose transport was 360 µM. The inhibitory effect of light chains was dose-dependent (r = 0.90, p < 0.0l for the λ-light chain and r = 0.93, p < 0.001 for the χ-light chain, on phosphate transport; and r = 0.93, p < 0.00l for glucose transport). Dixon and Line-weaver-Burk plot analyses were characteristic for noncompet-itive inhibition. The inhibition constant 89 µMfor phosphate uptake derived from the Dixon plot was similar to the IC50 calculated from the dose-response curves. These findings indicate that light chains, at concentrations found in the tubule fluid of a typical myeloma patient, are potent inhibitors of phosphate and glucose transport in proximal tubular cells, and that direct cell toxicity is a major mechanism of light chain neph