TOLERANCE INDUCED BY ALL-TRANS-RETINOL TO THE HEPATOTOXIC EFFECTS OF CADMIUM IN RATS - ROLE OF METALLOTHIONEIN EXPRESSION

Recently, it has been shown that large doses of all-trans-retinol (vit amin A) can potentiate the hepatotoxicity of several organic chemicals in the rat. Whether retinol pretreatment can alter the acute hepatoto xicity of an inorganic chemical, such as cadmium, is unknown. Therefor e, the objective of this study was to determine how retinol might affe ct the acute toxicity of cadmium chloride (CdCl2) and to elucidate pos sible mechanisms. Cadmium exposure can induce acute, lethal hepatocell ular necrosis in rodents, as well as lesions in the lung, kidney, test is, and gastrointestinal tract. In the present studies, male Sprague-D awley rats were pretreated with retinol (75 mg/kg/day, po) for 7 conse cutive days. One day after the last dose of retinol, animals were give n 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 postdos ing as evaluated by plasma enzymes and/or histopathology. In retinol-p retreated rats, a significant attenuation of CdCl2-induced tissue inju ry was observed. Since the inducible cadmium-binding protein metalloth ionein (MT) is often an essential aspect of cadmium tolerance, its con tent in tissue was assessed using the cadmium-hemoglobin assay. Intere stingly, retinol pretreatment significantly increased MT in the liver by sevenfold, but had no effect on lung, kidney, testicular, or pancre atic MT content. Although this increase in hepatic MT was much less th an that induced by CdCl2, it was additive to the induction of CdCl2. F urthermore, the tissue distribution of cadmium was significantly alter ed by retinol pretreatment. The liver accumulated more cadmium, while less cadmium was found in the lung, kidney, and testis in retinol-pret reated rats than in controls. In monolayers of primary isolated hepato cytes, CdCl2-induced toxicity was significantly reduced in cells isola ted from retinol-pretreated rats compared to those isolated from contr ol rats. The dose response was shifted to the right and the in vitro c admium LC50 was increased by in vivo retinol exposure from 1.1 +/- 0.1 to 2.4 +/- 0.04 mu M. From these data it is concluded that the induct ion of hepatic MT is an essential aspect of retinol-induced tolerance to CdCl2 hepatotoxicity, as well as toxicity in other tissues. (C) 199 7 Academic Press.