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Toxicologic Pathology
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Journal Article

Xenobiotic Metabolizing Enzymes of the Kidney

Edward A. Lock

Research Toxicology Section, Zeneca, Central Toxicology Laboratory, Alderley Park, Cheshire SK10 4TJ, United Kingdom

Celia J. Reed

School of Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, United Kingdom

The kidney possesses most of the common xenobiotic metabolizing enzymes, and is thus able to make an important contribution to the body's metabolism of drugs and foreign compounds. An overview of the renal localization, catalytic activity, developmental regulation, induction, and sex and species differences for the key enzymes involved in phase I and phase II of xenobiotic metabolism is presented. In general, the catalytic activities of the various renal enzymes are lower than those of the liver, although there are exceptions, such as the enzymes involved in the processing of glutathione conjugates to their mercapturic acids. Xenobiotic metabolizing enzymes are not evenly distributed along the nephron; cytochromes P-450 and those enzymes involved in the conjugation of glutathione, glucuronic acid, or sulfate are primarily localized in the proximal tubules. However, some isozymes of cytochrome(s) P-450 and glutathione S-transferases are selectively localized in cells of the thick ascending limb and distal tubules, whereas prostaglandin H synthase is concentrated in the collecting ducts in the medulla. Thus, the proximal tubule, the principal site of xenobiotic biotransformation, is particularly susceptible to chemical insult, and the localization of prostaglandin synthase in the inner medulla and papilla may be a contributary factor to the toxicity produced by chemicals in this part of the nephron. Many of the enzymes discussed, in addition to metabolizing foreign compounds, have important endogenous functions in the kidney, such as the regulation of salt and water balance and the synthesis of vitamin D.

Key Words: Renal cytochromes P-450 • renal glutathione S-transferases • renal glucuronosyl transferases • renal sulfotransferases • renal epoxide hydrolases • renal prostaglandin H synthase • renal cysteine conjugate β-Iyase • renal flavin monooxygenases

  • 1. Beckett GJ, Howie AF, Hume R, Matharoo B, Hiley C, Jones P, and Strange RC (1990). Human glutathione S-transferase: Radioimmunoassay studies on the expression of alpha-, mu-and pi-class isoenzymes in developing lung and kidney. Biochem. Biophys. Acta 1036: 979–986.
  • 2. Bodenham A, Quinn K, and Park GR (1989). Extrahepatic morphine metabolism in man during anhepatic phase of orthotopic liver transplantation. Br. J. Anaesth. 63: 380–384.[Abstract/Free Full Text]
  • 3. Commandeur JN, Stijntjes GJ, and Vermeulen NP (1995). Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role of bioactivation and detoxication mechanisms of xenobiotics. Pharmacol. Rev. 47: 271–330.[Web of Science][Medline] [Order article via Infotrieve]
  • 4. Coughtrie MWH (1992). Role of molecular biology in the structure and functional characterisation of UDP-glucuronosyltransferases. Prog. Drug Metab. 13: 35–71.
  • 5. Coughtrie MWH (1996). Sulphation catalysed by the human cytosolic sulphotransferases–-Chemical defence or molecular terrorism? Hum. Exp. Toxicol. 15: 547–555.[Free Full Text]
  • 6. Endou H (1983). Cytochrome P-450 monooxygenase system in the rabbit kidney: Intrancphron localisation and its induction Jpn. J. Pharmacol. 33: 423–433.[Medline] [Order article via Infotrieve]
  • 7. Grantham JJ and Chonko AM (1991). Renal handling of organic anions and cations: Excretion of uric acid. In: The Kidney, BM Brenner and FC Rector (eds). WB Saunders, Philadelphia, pp. 483–509.
  • 8. Grundemann D, Gorboulev V, Gambaryam S, Veyhl M, and Koepsell H (1994). Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372: 549–552.[CrossRef][Medline] [Order article via Infotrieve]
  • 9. Henderson CJ and Wolf CR (1991). Evidence that the androgen receptor mediates sexual differentiation of mouse renal P-450 expression. Biochem. J. 278: 499–503.[Web of Science][Medline] [Order article via Infotrieve]
  • 10. Henderson CJ and Wolf CR (1992). Molecular analysis of cytochromes P450's in the CYP2 gene family. Prog. Drug Metab. 13: 73–139.
  • 11. Hiley C, Bell J, Hume R, and Strange RC (1989). Differential expression of alpha and pi class isoenzymes of glutathione S-transferase in the developing human kidney. Biochem. Biophys. Acta 990: 321–324.[Medline] [Order article via Infotrieve]
  • 12. Hinchman CA and Ballatori N (1994). Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process. J. Toxicol. Environ. Health 41: 387–409.[Web of Science][Medline] [Order article via Infotrieve]
  • 13. Hines RN, Cashman JR, Philpot RM, Williams DE, and Ziegler DM. (1994). The mammalian flavin-containing monooxygenases: Molecular characterisation and regulation of expression. Toxicol. Appl. Pharmacol. 125: 1–6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 14. Jacqz E, Ward S, Johnson R, Schenker S, Gerkens J, and Branch RA (1986). Extrahepatic glucuronidation of morphine in the dog. Drug Metab. Dispos. 14: 627–630.[Abstract]
  • 15. Kaloyanides GJ (1991). Metabolic interactions between drugs and renal tubulointestitial cells: Role in nephrotoxicity. Kidney Int. 39: 531–540.[Web of Science][Medline] [Order article via Infotrieve]
  • 16. Kim HS, Cha SH, Abraham DG, Cooper AJL, and Endou H (1997). Intranephron distribution of cysteine conjugate β-lyase activity and its implication for hexachloro-1,3-butadiene-induced nephrotoxicity in rats. Arch. Toxicol. 71: 131–141.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 17. Krishna DR and Klotz U (1994). Extrahepatic metabolism of drugs in humans. Clin. Pharmacokinet. 26: 144–160.[Web of Science][Medline] [Order article via Infotrieve]
  • 18. Laniado-Schwartzman M and Abraham NG (1992). The renal cytochrome P-450 arachidonic system. Pediatr. Nephrol. 6: 490–498.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 19. Lock EA (1994). Renal drug metabolising enzymes in experimental animals and humans. In: Mechanisms of Injury in Renal Disease and Toxicity. RS Goldstein (ed). CRC Press, Boca Raton, Florida, pp. 173–206.
  • 20. Lock EA and Reed CJ (1997). Renal xenobiotic metabolism. In: Comprehensive Toxicology Part 7, RS Goldstein (ed). Pergamon Press, New York, pp. 77–97.
  • 21. Mazoit JX, Sandouk P, Zetlaoui P. and Scherrmann JM (1987). Pharmacokinetics of unchanged morphine in normal and cirrhotic subjects. Anesth. Analg. 66: 293–298.[Abstract/Free Full Text]
  • 22. McGiff JC (1991). Cytochrome P-450 metabolism of arachidonic acid. Annu. Rev. Pharmacol. Toxicol. 31: 339–369.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 23. Mosca M, Cozzi L, Breton J, Speciale C, Okuno E, Schwarcz R, and Benatti L. (1994). Molecular cloning of rat kynurenine aminotransferase: Identity with glutamine transaminase K. FEBS Lett. 353: 21–24.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 24. Murray GI, Barnes TS, Sewell HF, Ewen SWB, Melvin WT, and Burke MD (1988). The immunocytochemical localisation and distribution of cytochrome P-450 in normal hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br. J. Pharmacol. 25: 465–475.
  • 25. Pan J, Hong J-Y, and Yang CS (1992). Post-transcriptional regulation of mouse renal cytochrome P450 2E1 by testosterone. Arch. Biochem. Biophys. 15: 110–115.
  • 26. Perry SJ, Schofield MA, Harries H, Lock EA, King LJ, Gibson GG, and Goldfarb PS (1995). Molecular cloning and expression of a cDNA for human kidney cysteine conjugate β-lyase. FEBS Lett. 360: 277–280.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 27. Perry SJ, Schofield MA. MacFarlane M, Lock EA, King LJ, Gibson GG, and Goldfarb PS (1993). Isolation and expression of a cDNA coding for rat kidney cytosolic cysteine conjugate β-lyase. Mol. Pharmacol. 43: 660–665.[Abstract]
  • 28. Pinot F, Grant DF, Spearow JL, Parker AG, and Hammock BD (1995). Differential regulation of soluble epoxide hydrolase by clofibrate and sexual hormones in the liver and kidneys of mice. Biochem. Pharmacol. 50: 501–508.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 29. Rozell B, Hansson HA, Guthenburg C, Tahir MK, and Mannervik B (1993). Glutathione transferases of classes {alpha}, µ and {pi} show selective expression in different regions of rat kidney. Xenobiotica 23: 835–849.[Web of Science][Medline] [Order article via Infotrieve]
  • 30. Shehin-Johnson SE, Williams ED, Larsen-Su S, Stresser DM, and Hines RN (1995). Tissue specific expression of flavin containing monooxygcnase (FMO) forms 1 and 2 in the rabbit. J. Pharmacol. Exp. Ther. 272: 1293–1299.[Abstract/Free Full Text]
  • 31. Sipes IG and Gandolfi AJ (1991). Biotransformation of toxicants. In: Casarett and Doull's Toxicology. 4th ed., MO Amdur, J Doull, and CD Klaassen (eds). McGraw-Hill, New York, pp. 88–126.
  • 32. Sloan PA, Mather LE, McLean CF, Rutten AJ, Nation RL, Milne RW, Runciman WB, and Somogyi AA (1991). Physiological disposition of iv morphine in sheep. Br. J. Anaesth. 67: 378–386.[Abstract/Free Full Text]
  • 33. Smith BJ, Curtis JF, and Eling TE (1992). Bioactivation of xenobiotics by prostaglandin H synthase. Chem. Biol. Interact 79: 245–264.[CrossRef][Web of Science]
  • 34. Squires EJ and Negishi M (1990). Tissue specific regulation of cytochrome P-450 dependant testosterone 15{alpha}-hydroxylase. Can. J. Physiol. Pharmacol. 68: 769–776.[Web of Science][Medline] [Order article via Infotrieve]
  • 35. Stevens JL, Robbins JD, and Byrd RA (1986). A purified cysteine conjugate β-lyase from rat kidney cytosol. Requirement for an alpha-keto acid or an amino acid oxidase for activity and identity with soluble glutamine transaminase K. J. Biol. Chem. 261: 15529–15537.[Abstract/Free Full Text]
  • 36. Tarloff JB, Goldstein RS, and Hook JB (1987). Xenobiotic metabolism in the mammalian kidney. In: Nephrotoxicity in the Experimental and Clinical Situation. Part 1, PH Bach and EA Lock (eds). Martinus Nijhoff, Lancaster, United Kingdom, pp. 371–404.
  • 37. Tarloff JB, Goldstein RS, and Hook JB (1990). Xenobiotic metabolism in the mammalian kidney: Pharmacological and toxicological aspects. Prog. Drug Metab. 12: 1–39.
  • 38. Timbrell JA (1992). Factors affecting toxic responses: Metabolism. In: Principles of Biochemical Toxicology. Taylor and Francis, London, pp. 73–124.
  • 39. Waxman DJ, Dannan GA, and Guengerich FP (1985). Regulation of rat hepatic cytochrome P-450: Age-dependent expression, hormonal imprinting and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry 24: 4409–4417.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 40. Yan B, Yang D, Brady M, and Parkinson A (1994). Rat kidney carboxylesterase. Cloning, sequencing, cellular localisation and relationships to rat liver hydrolase. J. Biol. Chem. 269: 29688–29696.[Abstract/Free Full Text]
  • 41. Zenser TV, Mattammal MB, and Davis BB (1979). Demonstration of separate pathways for the metabolism of organic compounds in rabbit kidney. J. Pharmacol. Exp. Ther. 208: 418–421.[Free Full Text]

Toxicologic Pathology, Vol. 26, No. 1, 18-25 (1998)
DOI: 10.1177/019262339802600102
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This Article
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