Renal activation of trichloroethene andS‐(1,2‐dichlorovinyl)‐L‐cysteine and cell proliferative responses in the kidneys of F344 rats and B6C3F1 mice

Abstract

Covalent binding of reactive intermediates formed by renal beta-lyase activation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC) has been suggested to be responsible for the greater renal sensitivity of rats than mice to the carcinogenic effects of chronic treatment with trichloroethene (TRI). Previous work demonstrated that the activation of DCVC results in acid-labile adducts to protein that can be distinguished from adducts formed by other pathways of TRI metabolism. By analyzing acid-labile adduct formation, the relationship between DCVC formation and activation from TRI and increases in rates of cell division in the kidneys of male F344 rats and B6C3F1 mice could be investigated. The delivered dose of DCVC from an oral dose of 1000 mg/kg TRI was approximately six times greater in rats than mice. However, renal activation of DCVC in mice was approximately 12 times greater than in rats. Therefore, the overall activation of TRI was about two times greater in mice than rats. Induction of cell replication in liver and kidney following doses of 1, 5, or 25 mg/kg DCVC or 1000 mg/kg TRI was also measured through the use of miniosmotic pumps that delivered BrdU subcutaneously for 3 d. Acid-labile adduct formation from DCVC and TRI displayed a consistent relationship with increased cell replication in mice and between mice and rats. Both cell replication and acid-labile adduct formation in rats given 25 mg/kg DCVC were approximately equal to that observed in mice given 1 mg/kg. Increased cell replication was not observed in rats receiving 1 or 5 mg/kg DCVC or 1000 mg/kg TRI, nor were there histological signs of nephrotoxicity. Thus, net activation of TRI by the cysteine S-conjugate pathway was found to be greater in mice than rats and these findings appeared related to differences in cell proliferative responses of the kidneys of the two species. Based on these data, it would appear that other factors must contribute to the greater sensitivity of the rat to the induction of renal carcinogenesis by TRI.

Nephrotoxic effect of subchronic exposure to <i>S</i>-(1,2-dichlorovinyl)-<i>L</i>-cysteine in mice

“…Thus, many mechanistic studies of TCE-induced nephrotoxicity have focused on DCVC. The toxicity of DCVC has been well characterized in various animal models, including calves, dogs, cats, rabbits, guinea pigs, turkeys, rats and mice Eyre et al, 1995;Hassall et al, 1983;Krejci et al, 1991). With the exception of an investigation conducted by Terracini and Parker (1965), all the above-mentioned studies were examinations on short-term exposure to DCVC.…”

Metabolism of trichloroethylene.

“…While this would seem to make sense, as it is the quantity of the reactive species that is formed that can produce cellular injury and not, as discussed below, the quantity of stable endproducts that are excreted into the urine (e.g., mercapturates), the methodology is potentially complicated by artifacts due to chemical instability of the molecules being quantified. Additionally, Eyre et al (122,123) found that apparent net activation of TCE by the 1-lyase pathway and apparent acid-labile adduct formation were greater in mice than in rats, which does not correspond to the higher susceptibility of rats to renal toxicity and carcinogenesis, although adduct formation did correspond to increased cell replication rates. Hence, the relationship between adduct formation and effects on cellular function and homeostasis are very complex and require further study.…”

“…The initial 3-lyase activities that were purified from rat (115) and human (113) (122,123) suggested that measurement of the acid-labile adducts could be used as an index of flux through the ,B-lyase pathway. While this would seem to make sense, as it is the quantity of the reactive species that is formed that can produce cellular injury and not, as discussed below, the quantity of stable endproducts that are excreted into the urine (e.g., mercapturates), the methodology is potentially complicated by artifacts due to chemical instability of the molecules being quantified.…”

Effects of Genetic Polymorphisms of N-Acetyltransferase on Trichloroethylene-Induced Hypersensitivity Dermatitis among Exposed Workers

“…The effect of NAT2 genetic polymorphism on individual susceptibility to TCE-induced hypersensitivity dermatitis may be due to the lower NAT2 activity caused by gene mutation increase the metabolic flux through bioactivation catalyzed by β-lyase to produced large quantities of reactive intermediate. Eyre 36,37) . It is suggested that adducts could act as one of effective immune antigen which trigger abnormal immunological response and induced the hypersensitivity dermatitis.…”