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Titolo:
THE BIOACTIVATION OF AMODIAQUINE BY HUMAN POLYMORPHONUCLEAR LEUKOCYTES IN-VITRO - CHEMICAL MECHANISMS AND THE EFFECTS OF FLUORINE SUBSTITUTION
Autore:
TINGLE MD; JEWELL H; MAGGS JL; ONEILL PM; PARK BK;
Indirizzi:
UNIV LIVERPOOL,DEPT PHARMACOL & THERAPEUT,POB 147 LIVERPOOL L69 3BX MERSEYSIDE ENGLAND UNIV LIVERPOOL,DEPT PHARMACOL & THERAPEUT LIVERPOOL L69 3BX MERSEYSIDE ENGLAND
Titolo Testata:
Biochemical pharmacology
fascicolo: 7, volume: 50, anno: 1995,
pagine: 1113 - 1119
SICI:
0006-2952(1995)50:7<1113:TBOABH>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
INDUCED AGRANULOCYTOSIS; DRUG-REACTIONS; BONE-MARROW; MYELOPEROXIDASE; RAT; METABOLITES; DERIVATIVES; INHIBITION; LEUKOCYTES; ANTIBODIES;
Keywords:
AMODIAQUINE; BIOACTIVATION; POLYMORPHONUCLEAR LEUKOCYTES; FLUORINE SUBSTITUTION;
Tipo documento:
Note
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
31
Recensione:
Indirizzi per estratti:
Citazione:
M.D. Tingle et al., "THE BIOACTIVATION OF AMODIAQUINE BY HUMAN POLYMORPHONUCLEAR LEUKOCYTES IN-VITRO - CHEMICAL MECHANISMS AND THE EFFECTS OF FLUORINE SUBSTITUTION", Biochemical pharmacology, 50(7), 1995, pp. 1113-1119

Abstract

Amodiaquine, a 4-aminoquinoline antimalarial, has been associated with hepatitis and agranulocytosis in humans. Drug hypersensitivity reactions, especially agranulocytosis, have been attributed to reactive intermediates generated by the oxidants discharged from stimulated polymorphonuclear leucocytes (PMN). The metabolism of amodiaquine to both stable and chemically reactive metabolites by human PMN has been investigated in vitro. Incubation of [C-14]-amodiaquine with PMN resulted in irreversible binding of radiolabel to protein and depletion of intracellular reduced glutathione, which were enhanced by phorbol myristate acetate (PMA), a PMN activator. Two metabolites were identified: the C-5' glutathione adduct of amodiaquine, derived from both endogenous andexogenous glutathione, and 4-amino-7-chloroquinoline, which was presumed to be formed by hydrolysis of amodiaquine quinoneimine. Desethylamodiaquine, the major plasma metabolite of amodiaquine in humans, also underwent bioactivation to a chemically reactive species in the presence of PMA-stimulated PMN. Substitution of the Q-hydroxyl group in amodiaquine with fluorine significantly reduced irreversible binding to protein and abolished depletion of intracellular glutathione in the presence of PMA. These findings indicate that the bioactivation of amodiaquine by PMN is associated with the formation of a quinoneimine intermediate. Such a reactive metabolite, if produced in PMN or bone marrow in vivo, may be responsible for the drug's myelotoxicity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/07/20 alle ore 22:13:11