Kroll D J, Graichen M E, Leonard T B
Department of Drug Metabolism, Smith Kline and French Laboratories, King of Prussia, PA 19406-0939.
Carcinogenesis. 1988 Feb;9(2):193-8. doi: 10.1093/carcin/9.2.193.
Administration of the nephrotoxicant mercuric chloride (HgCl2) was found to increase microsomal epoxide hydrolase (EH) activity in the kidneys of Fischer 344 (F344) and Sprague-Dawley (SD) rats, but the increases observed were 2- to 4-fold greater in SD rats than in F344 rats. This study was designed to characterize HgCl2-mediated increases in renal EH activity, and to investigate possible biochemical mechanisms underlying the strain difference. In male SD rats killed 24 h after the last of three daily i.p. injections of HgCl2 (0.1-1 mg/kg), increases in renal EH activity were dose dependent, reaching a maximum of 550% of control. Renal EH activities in identically treated F344 rats were enhanced only to 200% of control values, however, the extent of nephrotoxicity was similar in both strains. Following a single HgCl2 treatment (1 mg/kg), maximal increases in renal EH activities were observed in SD rats (450% of control) at 3 days, and in F344 rats (225%) at 1-2 days. Hepatic glutathione (GSH) concentrations were unaffected by HgCl2 treatment, whereas renal GSH was slightly elevated in both strains. Hepatic metallothionein (MT) concentrations were increased at 1 day to 300% and 400% of control in F344 and SD rats, respectively. Maximal renal MT concentrations were observed at 2 and 3 days in F344 (300% of control) and SD (225%) rats, respectively. Pretreatment with Zn(OAc)2, a potent inducer of renal and hepatic MT, reduced the nephrotoxicity of HgCl2, but did not alter HgCl2-mediated renal EH increases in either strain. In addition, possible strain differences in 203HgCl2 distribution were assessed, but 203Hg distribution was similar in both strains. These studies have demonstrated that renal EH activity is induced by HgCl2, and that there is a strain difference in this response. Differences in MT, GSH and organ distribution of Hg do not account for the strain difference. The possibility remains that other, yet to be defined, protection pathways may exist. Alternatively, renal EH may be differentially regulated between the two strains.
