Uptake of nephrotoxic S-conjugates by isolated rat renal proximal tubular cells.
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)
Lash
L H
LH
Department of Pharmacology, University of Rochester School of Medicine and Dentistry, New York.
Anders
M W
MW
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012964:Sodium / Q000494:pharmacology
D006710:Homocysteine; C051126:S-(1,2-dichlorovinyl)homocysteine; D000625:Aminooxyacetic Acid; C039961:S-(1,2-dichlorovinyl)cysteine; D012964:Sodium; D003545:Cysteine; D011339:Probenecid