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The suppressed expression and functional activity of hepatic P-glycoprotein in rats with protein–calorie malnutrition

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ABSTRACT:

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 (Vmax) was decreased (35%, p < 0.05) by PCM, with constant affinity (Km), for the carrier-mediated uptake of daunomycin into cLPM vesicles, resulting in a 33% (p < 0.05) decrease in the intrinsic uptake clearance (CLint). The in vivo canalicular excretion clearance (CLexc) 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 (CLint). 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 CLexc. 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.

Section snippets

INTRODUCTION

Protein–calorie malnutrition (PCM) results from a variety of situations including the inability to eat, intestinal malabsorption, and several disease states including cancer, AIDS,1 liver dysfunction,2 chronic renal failure,3 tuberculosis,4 systemic inflammatory disease, and diabetes.1 PCM affects the pharmacokinetics and pharmacodynamics of furosemide5 and bumetanide,6 but the underlying mechanism(s) is poorly understood. PCM may alter basal metabolism and energy utilization in the liver in

Chemicals

[3H]-Daunomycin (4.4 Ci/mmol) was purchased from NEN Life Science Products (Boston, MA). All other chemicals were purchased from Sigma Chemical Co. (St. Louis, MO).

Animal Treatment

Male Sprague-Dawley rats (140–150 g in body weight; Dae-Han BioLink, Teajon, Korea) were purchased and maintained under filtered pathogen-free air and provided with water ad libitum. Experimental protocols involving animal studies were reviewed by the Animal Care and Use Committee of the College of Pharmacy, Seoul National University,

Pathophysiological Changes by PCM

Rats that were fed control protein diets showed more than a two-fold increase in body weight in 4 weeks [i.e., from 138 ± 6.8 to 309 ± 15 g (p < 0.01), mean ± SD, n = 12], whereas no such an increase was observed for rats fed with protein-restricted diets. This is consistent with the fact that less amounts of diets (approximately 49.9% as g/day/rat) were consumed by the PCM group compared with the control group. This indicates that the intake of protein and calorie(s) was decreased by 88.9 and 51.8%,

Acknowledgements

This study was supported by grant R01-2000-00180 from the Korea Science and Engineering Foundation, Republic of Korea.

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