Effects of N-(4-hydroxyphenyl)retinamide on vitamin A metabolism in rats

Chronic administration of the anticancer drug N-(4-hydroxyphenyl)-retinamide (4-HPR) causes reductions in the plasma levels of vitamin A and its transport protein, retinol-binding protein. Here, we used model-based compartmental analysis to study effects of 4-HPR on the whole-body kinetics of vitamin A metabolism in rats. Rats (n = 8) were fed a purified diet containing vitamin A (approximately 49 nmol retinol/day) plus 0 or approximately 50 mumole 4-HPR/(kg body wt.day). Plasma retinol kinetics were monitored for 35 days after intravenous administration of [3H]retinol-labeled plasma. 4-HPR caused an 80% reduction in plasma retinol; after 40 days of treatment with 4-HPR, liver vitamin A levels were 2.33 times higher than those of control rats. A three compartment model, in which plasma retinol exchanges with two extravascular compartments, was required to fit data for both groups. Vitamin A input was via the central plasma compartment, while irreversible loss was via the larger extravascular compartment. The time retinol spent in plasma before reversible or irreversible exit was normal (1.7 hr) in 4-HPR-treated rats, but the rate of plasma retinol turnover was reduced, and the recycling of retinol to plasma was delayed and reduced. Vitamin A utilization was significantly lower in 4-HPR-treated rats (20 nmol retinol/day vs 42 nmol/day in controls). We conclude that 4-HPR partially blocks access and thus binding of retinol to retinol-binding protein and may therefore lead to vitamin A accumulation in certain cells.