Reduced effect of microtubule inhibitors on hepatic protein secretion in the fetal rat

Drugs that block the assembly of microtubules inhibit protein secretion by mature hepatocytes. In this study, we ascertained the effects of these drugs on hepatic protein secretion during development. Slices prepared from adult and late-gestation (day 21) fetal rat livers were incubated with colchicine, vinblastine, or podophyllotoxin, and the secretion of [¹⁴C]leucine-labeled proteins was then determined. Colchicine (10 μM) decreased trichloroacetic acid-precipitable protein secretion by 65% in adult liver, but only by 31% in fetal liver. A higher (50 μM) concentration of colchicine caused minimal further impairment of secretion in both age groups. Colchicine (10 μM) impaired the secretion of immunoprecipitable albumin to about the same degree as trichloroacetic acid-precipitable proteins in both adult and fetus. Determinations of [³H]colchicine uptake into slices indicated that reduced hepatocellular levels of the drug were not the cause of the diminished effect on protein secretion observed in the fetus. Like colchicine, various concentrations of vinblastine and podophyllotoxin inhibited trichloroacetic acid-precipitable protein and albumin secretion consistently less from the fetal liver (30%-50%) than from the adult liver (50%-75%). These results indicate a reduced dependence on normal microtubule function for protein secretion in the developing liver.