Effects of triton WR 1339 and orotic acid on biliary and serum dolichols in rats

Abstract

Two lysosomal storage diseases, aspartylglucosaminuria and mannosidosis, are associated with highly elevated serum dolichol concentrations. To eludicate possible mechanisms leading to elevated serum dolichols, we studied the effects of Triton WR 1339 (known to increase serum cholesterol) and orotic acid (known to decrease serum cholesterol) on blood and biliary dolichol and beta-hexosaminidase levels in rats. In Triton WR 1339—treated rats, serum dolichol was markedly increased compared with saline-treated controls 1 (400 ± 70 ng/mL, n = 7 v 85 ± 11 ng/mL, n = 8, P < .001), 4 (789 ± 70 ng/mL, n = 10 v 110 ± 10 ng/mL, n = 7, P < .0001), and 8 (549 ± 43 ng/mL, n = 8 v 87 ± 8 ng/mL, n = 7, P < .001) days after administration of the drug. By contrast, serum dolichol was decreased (64 ± 5 ng/mL, n = 8 v 119 ± 7 ng/mL, n = 8, P < .0001) after a 7-day orotic acid feeding compared with controls. Serum beta-hexosaminidase was unaffected by both treatments. Orotic acid also increased biliary dolichol (280 ± 47 ng/100 g body weight [BW]/h, n = 7 v 83 ± 15 ng/100 g BW/h, n = 7, P < .01) and beta-hexosaminidase (21 ± 3 mU/100 g BW/h, n = 7 v 8.3 ± 2 mU/100 g BW/h, n = 9, P < .01) excretion compared with controls. Thus, both Triton WR 1339 and orotic acid have an effect on dolichol metabolism, and it is conceivable—based on our results—that serum dolichol concentrations are regulated, at least in part, by a mechanism similar to that for serum cholesterol levels.