The metabolism of 9-chloro-b-lapachone and its effects in isolated hepatocytes. 3 The involvement of NAD(P)H:quinone oxidoreductase 1 (NQO1)

FERNANDEZ VILLAMIL S H; CARRIZO P; DI ROSSO, M E; MOLINA PORTELA MP; DUBIN M

CHEMICO-BIOLOGICAL INTERACTIONS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2012 vol. 200 p. 84 - 91

0009-2797

A beta-lapachone analogue (3,4-dihydroxy-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione)(9-chloro b-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