Dietary orotic acid, a new selective growth stimulus for carcinogen altered hepatocytes in rat.

It was observed that orotic acid (OA), a precursor for pyrimidine nucleotide biosynthesis, when supplied exogenously at 1% level in the diet selectively stimulated the growth of hepatocytes modified by 1,2-dimethylhydrazine (1,2-DMH) to form gamma-glutamyltransferase (gamma-GT) (EC 2.3.2.2) positive islands. Increasing the duration of OA diet from 5 to 10 weeks resulted in an increase in the number of foci from 6 to 14/cm2. Rats that received the carcinogen and basal diet, however, developed only 1-2 foci/cm2. This unique effect of OA can be further accentuated by supplying a liver cell proliferative stimulus, such as a single necrogenic dose of CCl4.

Liver cell proliferation induced by a single dose of lead nitrate.

Treatment of male Wistar rats with a single dose of lead nitrate caused a marked enlargement of the liver, which reached its maximum 3 days after the administration of the metal salt. This grossly anatomic effect was accompanied by biochemical changes such as an increase in total protein and DNA content, with a maximum at 3 and 4 days, respectively. A partial regression of liver weight and total DNA and protein content occurred 7 days after lead administration; a significant increase in DNA concentration was found after 1 week, while no variation in protein, when expressed as milligrams per gram liver, was observed in lead-treated rat liver. An increase in DNA synthesis, as monitored by the incorporation of labeled thymidine, was also observed. An enhancement in the specific radioactivity of DNA was evident at 24 hours and appeared maximal at 36 hours after the administration of lead nitrate. The ability of lead to stimulate liver cell proliferation was shown by a significant increase of cells entering mitosis, with a peak at 48 hours. This mitogenic stimulus occurred in parenchymal as well as in nonparenchymal cells, thus showing that this effect was not unique to a particular liver cell populations. No detectable cell necrosis, as monitored by histologic observation, was seen in the liver of lead-treated rats, thus indicating that the cellular proliferation induced by lead is not due to a regenerative response. Only a slight elevation in the levels of serum glutamate-pyruvate transaminase (GPT) was observed by biochemical analysis.

Bromobenzene hepatotoxicity in lead pretreated rats.

We have studied the levels of hepatic GSH in animals intoxicated with bromobenzene. A marked decrease of hepatic GSH was observed in poisoned rats. Such decrease was prevented by previous administration of lead nitrate, an inhibitor of DMES. In the rats treated with lead nitrate alone a rise in hepatic GSH was observed. Such protection was further observed by histological examination. The mechanism of protection exerted by lead nitrate against bromobenzene intoxication is discussed.

Effect of glucose-6-phosphate dehydrogenase deficiency on the benz(a)pyrene toxicity for in vitro cultured human skin fibroblasts.

Human skin fibroblasts, isolated in vitro, from donors carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase, exhibit a sharp decrease of hexose monophosphate shunt and NADPH/NADP+ ratio when compared to the fibroblasts from normal donors. This behavior is coupled to an increase of the resistance to cell death and growth inhibition induced by benz(a)pyrene, whose activation proceeds through the NADPH-dependent arene oxide formation. No differences were observed in the toxic effects of methylnitrosourea, a carcinogen that does not need metabolic activation, on normal and variant fibroblasts.