title: The metabolism of 9-chloro-β-lapachone and its effects in isolated hepatocytes. The involvement of NAD(P)H:quinone oxidoreductase 1 (NQO1).
abstract: A β-lapachone analogue (3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione) (9-chloro β-lapachone), named CGQ, with antitumoral, antiviral and antitrypanocidal activities was assayed for cytotoxic effects on isolated rat hepatocytes. The incubation of hepatocytes with this o-naphthoquinone showed (a) decreased adenylate energy charge, as a result of a decrease in ATP, and an increase in AMP levels; (b) increased NADP(+) content, with a concomitant decrease of NADPH, NADH and NAD(+) content; (c) decreased GSH content, accompanied by an increase in GSSG formation; (d) stimulated oxygen uptake as well as increased superoxide anion production and hydrogen peroxide formation; (e) inhibited lipid peroxidation; (f) hepatocyte viability was not reduced unless the NQO1 inhibitor dicoumarol was present. We hypothesize that the cytotoxicity of CGQ in dicoumarol-treated hepatocytes was the result of inhibition of the NQO1 detoxification pathway, thus allowing more quinone to be metabolized towards the one-electron pathway to form reactive semiquinones and/or reactive oxygen species. The results obtained indicate a protective role of NQO1 in preventing CGQ cytotoxicity in isolated rat hepatocytes.
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina.
authors.forename: Silvia H
authors.initials: SH
authors.lastname: Fernandez Villamil
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Carrizo
authors.forename: Maria E
authors.initials: ME
authors.lastname: Di Rosso
authors.forename: Maria P
authors.initials: MP
authors.lastname: Molina Portela
authors.forename: Marta
authors.initials: M
authors.lastname: Dubin
mesh_terms: D000818:Animals; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C480829:3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho(1,2b)pyran-5,6-dione; D009285:Naphthoquinones; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat