The suppressed expression and functional activity of hepatic P-glycoprotein in rats with protein-calorie malnutrition.
The effect of protein-calorie malnutrition (PCM) on the expression and functional activity of P-glycoprotein (P-gp) in the liver of rats was examined. Control protein diets and protein-restricted diets were fed to Sprague-Dawley rats for 4 weeks, and the expression of P-gp in the liver (Western blot), in vitro uptake of a representative substrate of P-gp, daunomycin, into canalicular liver plasma membrane (cLPM) vesicles, and in vivo canalicular excretion of daunomycin were compared between the control and PCM rats. The expression of P-gp in the cLPM vesicles was decreased (22%, p < 0.05) by PCM. Consistent with this result, the in vitro uptake rate (V(max)) was decreased (35%, p < 0.05) by PCM, with constant affinity (K(m)), for the carrier-mediated uptake of daunomycin into cLPM vesicles, resulting in a 33% (p < 0.05) decrease in the intrinsic uptake clearance (CL(int)). The in vivo canalicular excretion clearance (CL(exc)) of daunomycin was also decreased by 79% (p < 0.01) in PCM rats, but the degree was more severe than would be expected from the 22% decrease in the expression of P-gp and the 33% decrease in the uptake of daunomycin (CL(int)). The hepatic level of adenosine 5'-triphosphate, which was decreased by 60% (p < 0.01) in PCM rats, might have contributed to this severe decrease in CL(exc). In summary, the canalicular excretion of P-gp substrates, such as daunomycin, might be reduced in patients with PCM via a mechanism involving the suppression of the expression of P-gp.
Lee
Young-Mi
YM
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Shinlim 9-dong, Kwanak-gu, Seoul 151-742, Korea.
Song
Im-Sook
IS
Kim
Sang Geon
SG
Lee
Myung Gull
MG
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology*; D000818:Animals; D031204:Caloric Restriction / Q000379:methods*; D018753:Diet, Protein-Restricted / Q000379:methods*; D008099:Liver / Q000378:metabolism*; D011502:Protein-Energy Malnutrition / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1