Altered cytochrome P450 and P-glycoprotein levels in rats during simulated weightlessness.
BACKGROUND
In order to investigate the effects of simulated weightlessness on drug metabolism, liver, kidney, and small intestine, microsomal proteins from tail-suspended rats were analyzed to determine cytochrome P450 (CYP) and P-glycoprotein levels following varying durations of tail-suspension.


OBJECTIVE
P-glycoprotein and CYP levels would both decrease similar to previous findings from actual spaceflight data.


METHODS
Six groups of four Sprague-Dawley rats each were tail-suspended for up to 21 d; CYP and P-glycoprotein levels in the liver, kidney and small intestine were then measured by Western blotting. The results were compared with a control group of unsuspended rats.


RESULTS
Our data showed there were significant changes in the levels of hepatic CYP2C11, 2E1, 4A1, and P-glycoprotein and significant changes in the levels of P-glycoprotein and CYP4A1 in the kidney. However, there were no significant changes detected in the levels of CYP3A2 in the liver or small intestine.


CONCLUSIONS
We conclude that simulated weightlessness, using the tail-suspended rat model, showed significant suppressive effects on levels of CYP2C11, 2E1, and P-glycoprotein in the liver and CYP4A1 in the kidney, while demonstrating no significant effect on the levels of CYP3A2 in the liver or small intestine. Thus, generalized predictions on the effect of simulated microgravity on drug metabolism cannot be made and the overall effect of spaceflight on individual enzymes should be investigated.
Lu
Shirley K
SK
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, 78712-1074, USA.
Bai
Shuang
S
Javeri
Khalid
K
Brunner
Lane J
LJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004734:Energy Metabolism / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D006899:Mixed Function Oxygenases / Q000378:metabolism; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D018474:Weightlessness Simulation / Q000009:adverse effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008565:Membrane Proteins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D042926:Cytochrome P-450 CYP4A