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Titolo:
Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes
Autore:
Haouzi, D; Lekehal, M; Moreau, A; Moulis, C; Feldmann, G; Robin, MA; Letteron, P; Fau, D; Pessayre, D;
Indirizzi:
Hop Beaujon, INSERM, U481, F-92118 Clichy, France Hop Beaujon Clichy France F-92118 , INSERM, U481, F-92118 Clichy, France Hop Beaujon, Ctr REch Hepatites Virales, Assoc Claude Bernard, F-92118 Clichy, France Hop Beaujon Clichy France F-92118 Claude Bernard, F-92118 Clichy, France Fac Med Xavier Bichat, INSERM, U327, Paris, France Fac Med Xavier Bichat Paris France Bichat, INSERM, U327, Paris, France Fac Pharmaceut Sci, Lab Pharmacognosie, Toulouse, France Fac Pharmaceut Sci Toulouse France Lab Pharmacognosie, Toulouse, France
Titolo Testata:
HEPATOLOGY
fascicolo: 2, volume: 32, anno: 2000,
pagine: 303 - 311
SICI:
0270-9139(200008)32:2<303:CPRMCM>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
HERBAL MEDICINE; CELL-DEATH; C RELEASE; HEPATOTOXICITY; GERMANDER; LIVER; DITERPENOIDS; INDUCTION; REMEDIES; BAX;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Pessayre, D Hop Beaujon, INSERM, U481, 100 Blvd Gen Leclerc, F-92118 Clichy, France Hop Beaujon 100 Blvd Gen Leclerc Clichy France F-92118 France
Citazione:
D. Haouzi et al., "Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes", HEPATOLOGY, 32(2), 2000, pp. 303-311

Abstract

Although cytochrome P-450 (CYP)-generated reactive metabolites can cause hepatocyte apoptosis, the mechanism of this effect is incompletely understood. In the present study, we assessed the hepatotoxicity of skullcap, a diterpenoid-containing herbal remedy. Male rat hepatocytes were incubated for 2hours with skullcap diterpenoids (100 mu g/mL). This treatment decreased cell glutathione and protein thiols and increased cell [Ca2+]. This activated Ca2+-dependent tissue transglutaminase, forming a cross-linked protein scaffold, and also opened the mitochondrial permeability transition pore, causing outer mitochondrial membrane rupture, increased cytosolic cytochrome c, activation of procaspase 3, internucleosomal DNA fragmentation, and ultrastructural features of apoptosis, Cell death was increased by a CYP3A inducer (dexamethasone) or a sulfur amino acid-deficient diet increasing glutathione depiction. In contrast, cell death was prevented by decreasing CYP3A activity (with troleandomycin), preventing glutathione depletion (with cysteine or cystine), blocking Ca2+-modulated events (with calmidazolium), preventing mitochondrial permeability transition (with cyclosporin A), or inhibiting caspase 3 (with acetyl-Asp-G u-Va-Asp-a dehyde). Both calmidazolium and cyclosporin A also prevented the increase in cytosolic cytochrome c and procaspase 3 activation. In conclusion, CYP3A activates skullcap diterpenoids into reactive metabolites that deplete cellular thiols and increase cell [Ca2+]. This activates Ca2+-dependent transglutaminase and also opens the mitochondrial permeability transition pore, causing outer mitochondrial membrane rupture, cytochrome c release, and caspase activation, Preventing mitochondrial permeability transition pore opening and/or caspase activity blocks apoptosis, showing the fundamental role of these final events in metabolite-mediated hepatotoxicity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/07/20 alle ore 08:45:08