EFFECT OF ARSENITE ON UREA PRODUCTION BY LONG-TERM CULTURES OF ADULT-RAT HEPATOCYTES

Urea cycle is a hepatic metabolic pathway involving five enzymes and s everal intermediary metabolites and can be altered by different chemic als. To investigate the effect of arsenic, an ubiquitous hepatotoxic a gent, on urea production we exposed long-term cultures of adult rat he patocytes, which produce urea, to 1.33 and 6.67 mu M arsenite for 2 we eks, In cultures exposed to 6.67 mu M, urea production decreased 60-70 % and cellular arginase activity decreased 30, 70 and 85% after 4, 7 a nd 14 days of exposure, respectively, The arginase activity released t o the medium increased significantly after 4, 7 and 14 days, with a ma ximum value after 7 days of exposure that was 27-fold higher than that of the untreated controls, The total arginase activity also decreased 35, 52 and 82% after 4, 7 and 14 days of exposure and protein content decreased 57 and 65% after 7 and 14 days of exposure, respectively, E xposure to 6.67 mu M arsenite also produced accumulation of intracytop lasmic lipid droplets, vacuolizations and enlargement of the intercell ular spaces, On the other hand, exposure of hepatocytes to 1.33 mu M a rsenite caused an initial decrease of 20% in urea production, did not change cellular, released and total arginase activity and cellular pro tein content and produced accumulation of intracytoplasmic lipid dropl ets, These results show that long-term exposure of cultured rat hepato cytes to 6.67 mu M arsenite decreases urea production, cellular and to tal arginase activity and protein content and increases the release of arginase into the culture medium, These alterations could be useful m arkers of hepatotoxicity in in vitro assays.