EFFECTS OF N-(4-HYDROXYPHENYL)RETINAMIDE ON VITAMIN-A METABOLISM IN RATS

Chronic administration of the anticancer drug N-(4-hydroxyphenyl)-reti namide (4-HPR) causes reductions in the plasma levels of vitamin A and its transport protein, retinol-binding protein. Here, we used model-b ased compartmental analysis to study effects of 4-HPR on the whole-bod y kinetics of vitamin A metabolism in rats. Rats (n = 8) were fed a pu rified diet containing vitamin A (similar to 49 nmol retinol/day) plus 0 or similar to 50 mu mole 4-HPR/(kg body wt.day), Plasma retinol kin etics were monitored for 35 days after intravenous administration of [ H-3]retinol-labeled plasma. 4-HPR caused an 80% reduction in plasma re tinol; after 40 days of treatment with 4-HPR, liver vitamin A levels w ere 2.33 times higher than those of control rats. A three compartment model, in which plasma retinol exchanges with two extravascular compar tments, was required to fit data for both groups. Vitamin A input was via the central plasma compartment, while irreversible loss was via th e larger extravascular compartment. The time retinol spent in plasma b efore reversible or irreversible exit was normal (1.7 hr) in 4-HPR-tre ated rats, but the rate of plasma retinol turnover was reduced, and th e recycling of retinol to plasma was delayed and reduced, Vitamin A ut ilization was significantly lower in 4-HPR-treated rats (20 nmol retin ol/day vs 42 nmol/day in controls). We conclude that 4-HPR partially b locks access and thus binding of retinol to retinol-binding protein an d may therefore lead to vitamin A accumulation in certain cells.