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Titolo:
IDENTIFICATION OF THE MAJOR HUMAN HEPATIC CYTOCHROME-P450 INVOLVED INACTIVATION AND N-DECHLOROETHYLATION OF IFOSFAMIDE
Autore:
WALKER D; FLINOIS JP; MONKMAN SC; BELOC C; BODDY AV; CHOLERTON S; DALY AK; LIND MJ; PEARSON ADJ; BEAUNE PH; IDLE JR;
Indirizzi:
UNIV NEWCASTLE UPON TYNE,SCH MED,DEPT PHARMACOL SCI NEWCASTLE TYNE NE2 4HH ENGLAND UNIV NEWCASTLE UPON TYNE,SCH MED,CANC RES UNIT NEWCASTLE TYNE NE2 4HHENGLAND UNIV NEWCASTLE UPON TYNE,SCH MED,DEPT CHILD HLTH NEWCASTLE TYNE NE2 4HH ENGLAND
Titolo Testata:
Biochemical pharmacology
fascicolo: 7, volume: 47, anno: 1994,
pagine: 1157 - 1163
SICI:
0006-2952(1994)47:7<1157:IOTMHH>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
OXIDATIVE DRUG-METABOLISM; HUMAN-LIVER; GENETIC-POLYMORPHISM; CYCLOPHOSPHAMIDE; RAT; PHARMACOKINETICS; 4-HYDROXYCYCLOPHOSPHAMIDE; PURIFICATION; CYCLOSPORINE; EXPRESSION;
Keywords:
CYTOCHROME P450 3A4; INHIBITION; NARINGENIN; TRIACETYLOLEANDOMYCIN; WESTERN BLOTTING; CORRELATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
D. Walker et al., "IDENTIFICATION OF THE MAJOR HUMAN HEPATIC CYTOCHROME-P450 INVOLVED INACTIVATION AND N-DECHLOROETHYLATION OF IFOSFAMIDE", Biochemical pharmacology, 47(7), 1994, pp. 1157-1163

Abstract

Two NADPH-dependent metabolic routes for the anticancer drug ifosfamide, 4-hydroxylation (activation) and N-dechloroethylation (a detoxication pathway),were studied in human liver microsomes to identify the cytochrome P450 enzymes involved. Naringenin, a grapefruit aglycone and an inhibitor of cytochrome P450 3A4 (CYP3A4)-catalysed reactions, was found to inhibit ifosfamide activation and N-dechloroethylation by human liver microsomes. IC50 for both reactions was of the order of 70 muM. The CYP3A4-specific inhibitor triacetyloleandomycin inhibited ifosfamide N-dechloroethylation by human Liver microsomes with an IC50 Of approximately 10 mu M. Furthermore, anti-human CYP3A4 antiserum inhibited by about 80% N-dechloroethylation of ifosfamide by human liver microsomes. The relative levels of cytochromes P450 1A, 2C, 2E and 3A4 in12 human livers were determined by western blotting analysis. A strong correlation (P < 0.001) was observed between CYP3A4 expression and both activation and N-dechloroethylation of ifosfamide. A role for human CYP3A4 in both pathways of ifosfamide metabolism was thus demonstrated. This was substantiated by the observation that the nifedipine oxidase activities of the 12 samples of human liver microsomes correlated with ifosfamide activation (P < 0.009) and N-dechloroethylation (P < 0.001). These findings have important clinical implications. The involvement of the same key cytochrome P450 enzyme in both reactions prohibits selective inhibition of the N-dechloroethylation pathway, as might be desirable to reduce toxic side effects. They also demonstrate the need to consider interaction with co-administered drugs that are CYP3A4substrates.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 06:26:10