Abstract
Purpose. The objective of this study was to investigate the mechanisms underlying the decrease in hepatic clearance of some drugs metabolized by CYP450 enzymes in chronic renal insufficiency (CRI).
Methods. CRI was induced in male Sprague-Dawley rats (n = 7) by the remnant kidney model (RKM); control animals (C) (n = 12) underwent sham surgery, of which n = 6 rats were pair-fed (CPF) with CRI rats and others (n = 6) had free access to food. Serum creatinine (Scr) and urea nitrogen (SUN) were monitored every 2 weeks. On day 36, livers were isolated, and microsomes were prepared. Catalytic activities were measured through O-demethylation (CYP2D) and N-demethylation of dextromethorphan (CYP3A) and O-deethylation of 7-ethoxyresorufin (CYP1A2). CYP450 protein and mRNA levels were also measured.
Results. Compared with CPF, Scr and SUN levels in CRI rats were increased twofold (p < 0.01) and 2.5-fold (p < 0.01), respectively. No effect on CYP1A2 and CYP2D activities, mRNA, or protein levels was observed between the groups. There was a reduction (41.8 ± 20%, p < 0.01) in CYP3A activity, mRNA (p < 0.05), and protein levels (p < 0.05) in CRI rats compared to CPF.
Conclusions. CRI induced by RKM does not have an effect on hepatic CYP1A2 and CYP2D enzymes but does reduce CYP3A activity, probably through down-regulation of CYP3A2.
Similar content being viewed by others
References
M. A. Touchette and R. L. Slaughter. The effect of renal failure on hepatic drug clearance. DICP 25:1214-1224 (1991).
L. Balant, R. J. Francis, T. N. Tozer, A. Marmy, J. M. Tschopp, and J. Fabre. Influence of renal failure on the hepatic clearance of bufuralol in man. J. Pharmacokinet. Biopharm. 8:421-438 (1980).
L. P. Balant, P. Dayer, and J. Fabre. Consequences of renal insufficiency on the hepatic clearance of some drugs. Int. J. Clin. Pharmacol. Res. 3:459-474 (1983).
A. Kanfer, G. Stamatakis, J. C. Torlotin, G. Fredj, S. Kenouch, and J. P. Mery. Changes in erythromycin pharmacokinetics induced by renal failure. Clin. Nephrol. 27:147-150 (1987).
R. Yuan and J. Venitz. Effect of chronic renal failure on the disposition of highly hepatically metabolized drugs. Int. J. Clin. Pharmacol. Ther. 38:245-253 (2000).
N. Gretz, R. Waldher, and M. Strauch. The remnant kidney model. In N. Gretz and M. Strauch (eds.), Experimental and Genetic Rat Models of Chronic Renal Failure. Karger, Basel, 1993, pp. 1-28.
A. P. Van Peer and F. M. Belpaire. Hepatic oxidative drug metabolism in rats with experimental renal failure. Arch. Int. Pharmacodyn. Ther. 228:180-183 (1977).
S. E. Patterson and V. H. Cohn. Hepatic drug metabolism in rats with experimental chronic renal failure. Biochem. Pharmacol. 33:711-716 (1984).
N. Uchida, N. Kurata, K. Shimada, Y. Nishimura, K. Yasuda, M. Hashimoto, E. Uchida, and H. Yasuhara. Changes of hepatic microsomal oxidative drug metabolizing enzymes in chronic renal failure (CRF) rats by partial nephrectomy. Jpn. J. Pharmacol. 68:431-439 (1995).
F. A. Leblond, L. Giroux, J. P. Villeneuve, and V. Pichette. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab. Dispos. 28:1317-1320 (2000).
B. Rege, C. March, and M. A. Sarkar. Development of a rapid and sensitive high-performance liquid chromatographic method to determine CYP2D6 phenotype in human liver microsomes. Biomed. Chromatogr. 16:31-40 (2002).
J. Ducharme, S. Abdullah, and I. W. Wainer. Dextromethorphan as an in vivo probe for the simulataneous determination of CYP2D6 and CYP3A4 activity. J Chromatogr B 678:113-128 (1996).
A. Yu and R. L. Haining. Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities? Drug Metab. Dispos. 29:1514-1520 (2001).
M. Kohzuki, M. Kamimoto, X. M. Wu, H. L. Xu, T. Kawamura, N. Mori, M. Nagasaka, H. Kurosawa, N. Minami, M. Kanazawa, T. Saito, and K. Yoshida. Renal protective effects of chronic exercise and antihypertensive therapy in hypertensive rats with chronic renal failure. J. Hypertens. 19:1877-1882 (2001).
K. A. Griffin, M. Picken, G. L. Bakris, and A. K. Bidani. Comparative effects of selective T-and L-type calcium channel blockers in the remnant kidney model. Hypertension 37:1268-1272 (2001).
P. D. Dass, E. W. Holmes, and E. W. Bermes. Hepatic and renal regulation of metabolite flow in the remnant kidney model of chronic renal failure. Contrib. Nephrol. 92:93-102 (1991).
R. J. Krieg, Jr., K. Latta, K. Niimi, J. D. Veldhuis, and J. C. Chan. Impact of uraemia on food efficiency and the pulsatile mode of growth hormone secretion in rats. J. Endocrinol. 146:509-517 (1995).
F. Santos, J. C. Chan, R. J. Krieg, K. Niimi, J. D. Hanna, M. D. Wellons, and L. F. Poletti. Growth hormone secretion from pituitary cells in chronic renal insufficiency. Kidney Int. 41:356-360 (1992).
H. O. Sohn, H. B. Lim, Y. G. Lee, D. W. Lee, and K. B. Lee. Modulation of cytochrome P-450 induction by long-term food restriction in male rats. Biochem. Mol. Biol. Int. 32:889-896 (1994).
P. Greenspan and J. Baron. Effect of unilateral nephrectomy on in vitro hepatic microsomal oxidative drug metabolism in the rat. Proc. Soc. Exp. Biol. Med. 164:307-311 (1980).
F. Leblond, C. Guevin, C. Demers, I. Pellerin, M. Gascon-Barre, and V. Pichette. Downregulation of hepatic cytochrome P450 in chronic renal failure. J. Am. Soc. Nephrol. 12:326-332 (2001).
E. Jacqz-Aigrain, C. Funck-Brentano, and T. Cresteil. CYP2D6-and CYP3A-dependent metabolism of dextromethorphan in humans. Pharmacogenetics 3:197-204 (1993).
J. Wan, S. Imaoka, T. Chow, T. Hiroi, Y. Yabusaki, and Y. Funae. Expression of four rat CYP2D isoforms in Saccharomyces cerevisiae and their catalytic specificities. Arch. Biochem. Biophys. 348:383-390 (1997).
T. Chow, S. Imaoka, T. Hiroi, and Y. Funae. Developmental changes in the catalytic activity and expression of CYP2D isoforms in the rat liver. Drug Metab. Dispos. 27:188-192 (1999).
N. Terao and D. D. Shen. Pharmacokinetics of l-propranolol during repetitive dosing in normal and uranyl nitrate-induced renal failure rats. J. Pharmacokinet. Biopharm. 12:479-493 (1984).
J. Bergstrom, M. Ahlberg, A. Alvestrand, and P. Furst. Amino acid therapy for patients with chronic renal failure. Infusionsther. Klin. Ernahr. 14(Suppl 5):8-11 (1987).
S. Ringoir, A. Schoots, and R. Vanholder. Uremic toxins. Kidney Int. Suppl. 24:S4-S9 (1988).
D. R. Nelson, L. Koymans, T. Kamataki, J. J. Stegeman, R. Feyereisen, D. J. Waxman, M. R. Waterman, O. Gotoh, M. J. Coon, R. W. Eastbrook, I. C. Gunsalus, and D. W. Nebert. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1-42 (1996).
P. A. Hoen, J. N. Commandeur, N. P. Vermeulen, T. J. Van Berkel, and M. K. Bijsterbosch. Selective induction of cytochrome P450 3A1 by dexamethasone in cultured rat hepatocytes: analysis with a novel reverse transcriptase-polymerase chain reaction assay section sign. Biochem. Pharmacol. 60:1509-1518 (2000).
T. Oinonen, S. Saarikoski, K. Husgafvel-Pursiainen, A. Hirvonen, and K. O. Lindros. Pretranslational induction of cytochrome P4501A enzymes by beta-naphthoflavone and 3-methylcholanthrene occurs in different liver zones. Biochem. Pharmacol. 48:2189-2197 (1994).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rege, B., Krieg, R., Gao, N. et al. Down-Regulation of Hepatic CYP3A in Chronic Renal Insufficiency. Pharm Res 20, 1600–1606 (2003). https://doi.org/10.1023/A:1026135317578
Issue Date:
DOI: https://doi.org/10.1023/A:1026135317578