Effect of sodium alterations on hepatic cytochrome P450 3A2 and 2C11 and renal function in rats.
Numerous dietary supplements are known to modulate cytochrome P450 (CYP)-mediated metabolism and subsequently alter drug toxicity or efficacy in animals and humans. In the present study we investigated the effect of varying amounts of sodium intake on renal function and the metabolic activity of the hepatic CYP3A2 and CYP2C11 isoforms. Rats were maintained on standard rodent chow or a low-salt rice diet. Within each of these groups rats received either a single intraperitoneal injection of furosemide to initiate salt depletion, or saline. Additional groups included salt supplementation of 500 mg/300 g body weight/day and 1.25 g/300 g body weight/day of sodium chloride solution. Rats receiving the low-salt diet, both with and without a concomitant furosemide administration, had a significant reduction in creatinine clearance without changes in serum creatinine. In addition, urine flow rate was markedly reduced in rats maintained on the low-salt diet. Western blot analysis indicated that neither sodium supplementation nor deprivation altered hepatic microsomal CYP3A2 levels; however, hepatic CYP2C11 levels significantly increased in rats receiving the largest sodium supplement. In vitro metabolic activity of CYP3A2 was unchanged as compared with controls. Activity of CYP2C11 was significantly reduced in both rat groups receiving additional sodium supplements. Acute manipulation of daily sodium intake does alter renal function and specific hepatic CYP isoforms and should be considered when using these rat models.
Liu
Jinrong
J
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712-1074, USA.
Callahan
Shellie M
SM
Brunner
Lane J
LJ
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004039:Diet, Sodium-Restricted / Q000009:adverse effects; D005665:Furosemide / Q000494:pharmacology*; D006955:Hypernatremia / Q000139:chemically induced / Q000378:metabolism; D007010:Hyponatremia / Q000139:chemically induced / Q000378:metabolism; D015151:Immunoblotting; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism*
D008565:Membrane Proteins; D012965:Sodium Chloride; D005665:Furosemide; D003577:Cytochrome P-450 Enzyme System; 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