14.03 - Renal Xenobiotic Metabolism

Abstract

The kidney possess most of the common drug-metabolising enzymes, and thus is able to make an important contribution to the body’s metabolism of drugs and other xenobiotics. The catalytic activity of the various enzymes is lower than in the liver, however enzymes involved in the processing of GSH conjugates to their mercapturic acids primarily involves the kidney. Xenobiotic-metabolising enzymes are not evenly distributed along the nephron: cytochromes P450 and enzymes involved in conjugation, glucuronidation or sulfation are present in higher concentrations in proximal tubular cells then other regions. There are however exception where some isoenzymes of P450 and GST’s are selectively localized in cells of the thick ascending limb. Most of the major form of cytochrome P450 are detected in the kidneys of experimental animals and humans. However, members of the CYP1 family, CYP2D6 and CYP2E1 appear to be, absent in human kidney. GST’s have been most extensively characterised in rat and humans kidney. The renal enzyme cysteine conjugate β-lyase involved in the bioactivation of haloalkane and haloalkene S-conjugates have been cloned and sequenced from both rat and human kidney and shown to be identical to glutamine transaminase K and KAT. Cloning approaches have also demonstrated the presence in the kidney of multiple forms of UGT, flavin monooxygenases, CES and SULTS. Bioactivation of certain chemicals by SULTS can generate reactive metabolites that modify DNA and leads to renal cancer. All of the enzymes discussed in addition to detoxification of foreign chemicals, and in a few case causing bioactivation have endogenous functions in the body. Such as regulation of salt and water balance, the control of blood pressure and synthesis of vitamin D and there are many more physiological roles for these enzymes awaiting discovery.