Search

The W/SSM rat strain with symptoms of inherited galactosemia (cataracts, hepatosplenomegaly, aminoaciduria etc.) was previously developed by selection and inbreeding of Wistar rats highly susceptible to the galactosemic effect of galactose. The decreased activity of galactose-1-phosphate uridyl transferase (Gal-1-PUT) in liver and erythrocytes is the salient biochemical feature of the strain. The crossing experiments have shown that the decrease in Gal-1-PUT activity is not a prerequisite for the expression of main galactosemia symptoms. The experiments excluded the low galactokinase activity and high susceptibility of glucoso-6-phosphate dehydrogenase and phosphoglucomutase to galactose-1-phosphate as probable causes of galactosemia. It was shown that the increased transport of 14C-galactose to erythrocytes is characteristic of the galactosemic rat strain. The intracellular accumulation of galactose concerned with its increased transport was assumed to be a major reason of the development of galactosemia symptoms in W/SSM rats. Genetic analysis has shown that lens lesions in galactosemic rats are controlled by one dominant gene. It is suggested that this gene is responsible for the enhanced transport of galactose into the rat cells and its accumulation in toxic concentrations. The main galactosemic symptoms, including cataracts, result obviously from the pleiotropic effect of this gene, while the decreased activity of Gal-1-PUT may be a consequence of its epistatic effect.

Feeding of rats with galactose-rich ration results in the activation of galactoso-1-phosphate-uridililtransferase in the liver after 2--4 days. By days 5--13, the activity of the enzyme decreased to the control level in spite of continued feeding of rats with galactose-rich ration. The activation of galactoso-1-phosphate-uridililtransferase occurred on the first 5 days of the experiment, whereas all proliferative activity in the liver increased from days 12--60, and the maximum mitotic was attained by the 20th and 50th days of feeding with galactose-rich diet. DNA synthesis also increased considerably, and this evidenced the increased H3-thymidine incorporation in hepatocyte nuclei. If one accept that the induction of enzyme transforming galactose to glucose is an adaptive response of cells (organism) to galactose in the diet, then the subsequent stage of adaptation would be hepatocyte proliferation.

A W/SSM rat strain with symptoms of inherited galactosemia (cataracts, hepatosplenomegaly, aminoaciduria) was previously developed by selection and inbreeding of Wistar rats highly susceptible to the galactosemic effect of galactose. Decreased activity of galactose-I-phosphate uridyl transferase (Gal-I-PUT) in liver and erythrocytes is the salient biochemical feature of the strain. The crossing experiments have shown that the decrease in Gal-I-PUT activity was not required for the expression of main galactosemia symptoms. The experiments excluded low galactokinase activity and high susceptibility of glucose-6-phosphate dehydrogenase and phosphoglucomutase to galactose-I-phosphate as probable reasons of galactosemia. It was shown that increased transport of 14C-galactose to the erythrocytes was characteristic of galactosemic rat strain. The intracellular accumulation of galactose concerned with its increased transport was assumed as a major reason for the development of galactosemia symptoms in W/SSM rats. Genetic analysis has shown that lens lesions in galactosemic rats were controlled by one dominant gene. It is suggested that this gene is responsible for the enhances transport of galactose into the rat cells and its accumulation in toxic concentrations. The main galactosemic symptoms including cataracts result obviously rom the pleiotropic effect of this gene; the decreased activity of Gal-I-PUT may be a consequence of its epistatic effect.

It was established earlier that the maintenance of rats on a galactose-rich diet induced in rat liver a sequental induction of enzymes, converting galactose to glucose (galactokinase, galactoso-1-phosphaturidytransferase and uridyndiphosphogalactose-4-epimerase); this was followed by the repression of these enzymes. Against the background of the enzyme repression, the continuation of galactose treatment leads to the development of galactosemia symptoms; cataracts, liver lesions growth retardation. Animals with the increased susceptibility to galactose were found in population of Wistar rats; in these animals rapidly developing enzyme induction is followed by sharp repression of enzymes of the galactose metabolism and in them cataracts appear 17-19 days after the start of feeding a galactose-rich diet. A part of the population is resistant to the galactosemic effect of galactose and in these animals cataracts develope only 40-44 days after the beginning of the galactose feeding. By inbreeding of individuals extremely susceptible to galactose and those resistant to it, new substrains of rats were obtained. It is found that in the rats of the galactose-susceptible substrain a number of galactosemic features develope spontaneously and that these features are inheritable. Thus, 85% of the animals of the age of 2.5-6 months have cataract, lens opacities and other lens impairments. In the galactose-resistant substrain no cataracts or lens opacities develope and only slight changes of the lens are observed in 15% of the animals. In the susceptible substrain other features characteristic of galactosemia occur: an increase in the size of thymus, spleen and liver. It is established that in 3.5-5 month old rats of the galactose-susceptible substrain the galactoso-1 phosphaturidyltransferase activity in blood hemolysates is 15 times lower than in rats of galactose-resistant substrain, and in liver the activity of this enzyme is 1.4 times lower. The activity of liver galactokinase and uridyldiphosphogalactose-4-epimerase is slightly higher in rats of galactose-susceptible substrain than in galactose-resistant 1.