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LH Lash and MW Anders
Department of Pharmacology, University of Rochester School of Medicine and Dentistry, New York.
Freshly isolated, rat renal proximal tubular cells have been widely used to study the biochemical mechanisms of cysteine and homocysteine S- conjugate-induced cytotoxicity. Because cellular transport may be an important determinant of S-conjugate-induced nephrotoxicity, the characteristics of the transport of nephrotoxic cysteine S-conjugates and analogs were studied in rat renal proximal tubular cells. Time- and concentration-dependent uptake of S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) into cells were observed; higher concentrations were accumulated in the presence of aminooxyacetic acid (AOAA), an inhibitor of cysteine conjugate beta- lyase, indicating that AOAA does not inhibit transport. Saturable sodium-dependent and sodium-independent transport processes were identified; approximately 50% of DCVC uptake, but only 30% of DCVHC uptake, was sodium-dependent. Competition studies indicated that the probenecid-sensitive organic anion transport system, which is sodium- dependent, and system L, which is sodium-independent, participate in the renal proximal tubular uptake of both S-conjugates. In addition, DCVHC uptake occurs by the sodium-dependent system ASC and system A. The greater degree of sodium independence of DCVHC uptake as compared to that of DCVC indicates that system L plays a greater role in DCVHC uptake than it does in DCVC uptake. Both sodium-dependent and sodium- independent uptake of the nonmetabolizable and nontoxic alpha-methyl analogs, S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine and S-(1,2- dichlorovinyl)-DL-alpha-methylhomocysteine, were observed at rates comparable to those of DCVC and DCVHC.(ABSTRACT TRUNCATED AT 250 WORDS)
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