title: Tolerance induced by all-trans-retinol to the hepatotoxic effects of cadmium in rats: role of metallothionein expression.
abstract: Recently, it has been shown that large doses of all-trans-retinol (vitamin A) can potentiate the hepatotoxicity of several organic chemicals in the rat. Whether retinol pretreatment can alter the acute hepatotoxicity of an inorganic chemical, such as cadmium, is unknown. Therefore, the objective of this study was to determine how retinol might affect the acute toxicity of cadmium chloride (CdCl2) and to elucidate possible mechanisms. Cadmium exposure can induce acute, lethal hepatocellular necrosis in rodents, as well as lesions in the lung, kidney, testis, and gastrointestinal tract. In the present studies, male Sprague-Dawley rats were pretreated with retinol (75 mg/kg/day, po) for 7 consecutive days. One day after the last dose of retinol, animals were given a single injection of CdCl2 (2.5 to 4.0 mg/kg, iv). Cadmium chloride administration to unpretreated control rats caused extensive hepatic, renal, pulmonary, and testicular toxicity at 6, 24, and 48 hr postdosing as evaluated by plasma enzymes and/or histopathology. In retinol-pretreated rats, a significant attenuation of CdCl2-induced tissue injury was observed. Since the inducible cadmium-binding protein metallothionein (MT) is often an essential aspect of cadmium tolerance, its content in tissue was assessed using the cadmium-hemoglobin assay. Interestingly, retinol pretreatment significantly increased MT in the liver by sevenfold, but had no effect on lung, kidney, testicular, or pancreatic MT content. Although this increase in hepatic MT was much less than that induced by CdCl2, it was additive to the induction of CdCl2. Furthermore, the tissue distribution of cadmium was significantly altered by retinol pretreatment. The liver accumulated more cadmium, while less cadmium was found in the lung, kidney, and testis in retinol-pretreated rats than in controls. In monolayers of primary isolated hepatocytes, CdCl2-induced toxicity was significantly reduced in cells isolated from retinol-pretreated rats compared to those isolated from control rats. The dose response was shifted to the right and the in vitro cadmium LC50 was increased by in vivo retinol exposure from 1.1 +/- 0.1 to 2.4 +/- 0.04 microM. From these data it is concluded that the induction of hepatic MT is an essential aspect of retinol-induced tolerance to CdCl2 hepatotoxicity, as well as toxicity in other tissues.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, 85721-0207, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Sauer
authors.forename: M P
authors.initials: MP
authors.lastname: Waalkes
authors.forename: S B
authors.initials: SB
authors.lastname: Hooser
authors.forename: A T
authors.initials: AT
authors.lastname: Baines
authors.forename: R K
authors.initials: RK
authors.lastname: Kuester
authors.forename: I G
authors.initials: IG
authors.lastname: Sipes
mesh_terms: D000818:Animals; D002104:Cadmium / Q000032:analysis; D019256:Cadmium Chloride / Q000493:pharmacokinetics; D002478:Cells, Cultured / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D007275:Injections, Intravenous; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution; D014801:Vitamin A / Q000008:administration & dosage*
chemical_list: D002104:Cadmium; D014801:Vitamin A; D008668:Metallothionein; D007770:L-Lactate Dehydrogenase; D019256:Cadmium Chloride