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Titolo:
HUMAN KIDNEY METHOXYFLURANE AND SEVOFLURANE METABOLISM - INTRARENAL FLUORIDE PRODUCTION AS A POSSIBLE MECHANISM OF METHOXYFLURANE NEPHROTOXICITY
Autore:
KHARASCH ED; HANKINS DC; THUMMEL KE;
Indirizzi:
UNIV WASHINGTON,DEPT ANESTHESIOL,RN-10 SEATTLE WA 98195 UNIV WASHINGTON,DEPT MED CHEM SEATTLE WA 98195 UNIV WASHINGTON,DEPT PHARMACEUT SEATTLE WA 98195
Titolo Testata:
Anesthesiology
fascicolo: 3, volume: 82, anno: 1995,
pagine: 689 - 699
SICI:
0003-3022(1995)82:3<689:HKMASM>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; PLASMA INORGANIC FLUORIDE; IMMUNOCYTOCHEMICAL LOCALIZATION; ENFLURANE DEFLUORINATION; COUMARIN 7-HYDROXYLATION; EXTRAHEPATIC TISSUES; ISOFLURANE SEDATION; STRAIN DIFFERENCES; DRUG-METABOLISM; RENAL-FUNCTION;
Keywords:
ANESTHETICS, VOLATILE, ENFLURANE ISOFLURANE METHOXYFLURANE SEVOFLURANE; IONS, FLUORIDE; KIDNEY, METABOLISM; LIVER, METABOLISM; METABOLISM, DRUG, CYTOCHROME P450; TOXICITY, FLUORIDE METABOLITES RENAL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
55
Recensione:
Indirizzi per estratti:
Citazione:
E.D. Kharasch et al., "HUMAN KIDNEY METHOXYFLURANE AND SEVOFLURANE METABOLISM - INTRARENAL FLUORIDE PRODUCTION AS A POSSIBLE MECHANISM OF METHOXYFLURANE NEPHROTOXICITY", Anesthesiology, 82(3), 1995, pp. 689-699

Abstract

Background: Methoxyflurane nephrotoxicity is mediated by cytochrome P450-catalyzed metabolism to toxic metabolites. It is historically accepted that one of the metabolites, fluoride, is the nephrotoxin, and that methoxyflurane nephrotoxicity is caused by plasma fluoride concentrations in excess of 50 mu M. Ssvoflurane also is metabolized to fluoride ion, and plasma concentrations may exceed 50 mu M, yet sevoflurane nephrotoxicity has not been observed. It is possible that in situ renal metabolism of methoxyflurane, rather than hepatic metabolism, is a critical event leading to nephrotoxicity. We tested whether there was ametabolic basis for this hypothesis by examining the relative rates of methoxyflurane and sevoflurane defluorination by human kidney microsomes. Methods: Microsomes and cytosol were prepared from kidneys of organ donors. Methoxyflurane and sevoflurane metabolism were measured with a fluoride-selective electrode. Human cytochrome P450 isoforms contributing to renal anesthetic metabolism were identified by using isoform-selective inhibitors and by Western blot analysis of renal P450s inconjunction with,metabolism by individual P450s expressed from a human hepatic complementary deoxyribonucleic acid library.Results: Swvoflurane and methoxyflurane did undergo defluorination by human kidney microsomes. Fluoride production was dependent an time, reduced nicotinamide adenine dinucleotide phosphate, protein concentration, and anesthetic concentration. In seven human kidneys studied, enzymatic sevoflurane defluorination was minimal, whereas methoxyflurane defluorination rates were substantially greater and exhibited large interindividual variability. Kidney cytosol did not catalyze anesthetic defluorination. Chemical inhibitors of the P450 isoforms 2E1, 2A6, and 3A diminished methoxyflurane and sevoflurane defluorination. Complementary deoxyribonucleic acid-expressed P450s 2E1, 2A6, and 3A4 catalyzed methoxyflurane and sevoflurane metabolism, in diminishing order of activity. These three P450s catalyzed the defluorination of methoxyflurane three to ten times faster than they did that of sevoflurane. Expressed P450 2B6 also catalyzed methoxyflurane defluorination, but 2B6 appeared not to contribute to renal microsomal methoxyflurane defluorination because the P450 2B6-selective inhibitor had no effect. Conclusions: Human kidney microsomes metabolize methoxyflurane, and to a much lesser extent sevoflurane, to fluoride ion. P450s 2E1 and/or 2A6 and P450 3A are implicated in the defluorination. If intrarenally generated fluoride or othermetabolites are nephrotoxic, then renal metabolism may contribute to methoxyflurane nephrotoxicity. The relative paucity of renal sevoflurane defluorination may explain the absence of clinical sevoflurane nephrotoxicity to date, despite plasma fluoride concentrations that may exceed 50 mu M.

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Documento generato il 10/07/20 alle ore 03:09:53