Galactose metabolism in mice with galactose-1-phosphate uridyltransferase deficiency: Sucklings and 7-week-old animals fed a high-galactose diet

Mice deficient in galactose-1-phosphate uridyl-transferase (GALT) demonstra te abnormal galactose metabolism but no obvious clinical phenotype. To furt her dissect the pathways of galactose metabolism in these animals, galactos e oxidation and metabolite levels were studied in 16 day-old sucklings and the effect of a 4 week prior exposure to a 40% glucose or 40% galactose die t was determined in 7-week-old mice. Suckling GALT-deficient (G/G) mice slo wly oxidized [1-C-14]galactose to (CO2)-C-14, 4.0% of the dose when fed and 7.9% when fasted compared to normal animals 38.3 and 36.4% in 4 h, respect ively. Plasma of G/G sucklings contained 11.1 mM galactose and erythrocyte galactose 1-phosphate levels were 28.2 and 31.9 mg/dl packed cells. Galacto se, galactitol, galactonate, and galactose 1-phosphate were found in G/G su ckling mouse tissues. The tissue galactose concentrations were 10% or less of that in plasma, suggesting that there was limited cellular entry of gala ctose. In 7-week-old fasted mice with 4 weeks prior exposure to glucose or galactose-containing diet, 4-h oxidation was 12.9 and 15.0% of the administ ered radiolabeled galactose, respectively. Normal animals oxidized 33.9 and 37.9% of the dose when fed the same diets, respectively. The ability of G/ G mice to oxidize galactose in the absence of GALT activity suggests the pr esence of alternate metabolic pathways for galactose disposition. G/G; mice fed the galactose-free 40% glucose diet had erythrocyte galactose 1-phosph ate levels ranging from 6.4 to 17.7 mg/dl packed cells and detectable galac tose and galactose metabolites in tissues, suggesting that these animals en dogenously produced galactose. The plasma of 40% galactose-fed G/G mice con tained 9.1 mM galactose with red blood cell galactose 1-phosphate averaging 43.6 mg/dl. Tissues of these animals also contained high levels of galacto se and galactose 1-phosphate. Liver contained over 4 mu mol/g galactonate b ut little galactitol. Despite the elevated galactose and galactose 1-phosph ate, the animals tolerated the high-galactose diet and were indistinguishab le from normal animals, exhibiting no manifestations of galactose toxicity seen in human GALT-deficient galactosemia, The data suggest that high galac tose 1-phosphate levels do not cause galactose toxicity and that high galac titol in combination with galactose 1-phosphate may be a prerequisite. Abse nce of GALT appears necessary but insufficient to produce human galactosemi c phenotype. (C) 2001 Academic Press.