Renal Xenobiotic Metabolism

Abstract

All of the common drug-metabolizing enzymes involved in phase 1 and phase 2 metabolism of xenobiotics are present in the kidney, although the catalytic activity of the various enzymes in the whole kidney is lower than that in the liver. Renal drug-metabolizing enzymes are, however, not evenly distributed along the nephron; cytochrome’s P450 and enzymes involved in conjugation with glutathione (GSH), glucuronic acid, or sulfate are present at much higher concentrations in cells of the proximal tubule than in other parts of the nephron, and thus comparison on a whole organ basis underestimates renal cell activity. Hence, the proximal tubule is the principal site of xenobiotic biotransformation and is particularly susceptible to chemical insult, while the localization of prostaglandin H-synthase (PHS) to the inner medulla and papilla may be a contributory factor to the toxicity produced by chemicals in this part of the nephron. Many xenobiotic-biotransformation enzymes have been cloned and sequenced, and their presence in the kidney detected. Most of the major families of cytochrome P450 involved in xenobiotic metabolism have been detected in the kidneys of experimental animals and humans. Members of the CYP2B subfamily appear to be absent from rat and mouse kidney but present in the rabbit and hamster. The CYP4A subfamily involved in ω and ω–1 oxidation of fatty acids and arachidonic acid (AA) are expressed at particularly high levels in the kidney and are involved in the side chain metabolism of many drugs and xenobiotics. Glutathione S-transferases (GSTs) have been most extensively characterized in rat and human kidney, this tissue having a different subunit profile from that of the liver, with a predominance of A (alpha) and P1-1 (pi) classes. Cloning has identified a number of relatively new forms of GSTs, and although these enzymes are mainly located in the cytosol, some are associated with microsomes and mitochondria. The kidney plays a pivotal role in the processing of GSH conjugates to their cysteine conjugates and then mercapturic acids for excretion in urine. The renal enzyme cysteine conjugate β-lyase involved in the bioactivation of haloalkane and haloalkene S-cysteine conjugates has been cloned and sequenced from both rat and human kidney, and is shown to be identical to glutamine transaminase K and kynurenine aminotransferase. Cloning approaches have also demonstrated the presence in the kidney of multiple forms of UDP-glucuronosyltransferase, flavin monooxygenase, carboxylesterase, and sulfotransferase The presence and localization of xenobiotic biotransformation enzymes in human kidney are still limited, although information on embryonic and fetal tissue is beginning to emerge. Many of the enzymes discussed, in addition to their ability to metabolize drugs or foreign compounds, have endogenous functions in the kidney, for instance, in the regulation of salt and water balance, the control of blood pressure and inflammation, and the synthesis of vitamin D.