Dapsone-induced toxicity in hepatic human cells lines is attenuated by antioxidants: Possible role of CYP450-mediated dapsone metabolism

VEGGI L.M.; ROMA M.G.; MOTTINO A.D.; COLEMAN M.D.

Córdoba

Congreso; XXXVIII Reunión de la Sociedad Argentina de Farmacología Experimental; 2006

Sociedad Argentina de Farmacología Experimental (SAFE)

Dapsone (DDS) is the main therapeutic agent for leprosy. Clinical experience has indicated that DDS may cause hepatotoxicity. Activation of the drug to dapsone hydroxylamine (DDS-OH), by CYP450 isoenzymes is cause of hemotoxicity. We examined the role of oxidative stress in DDS- and DDS-OH-induced toxicity in human liver cell lines. SK-Hep1 and HepG2, cultured in micro-plates, were exposed to DDS (0,23, 0,31, 0,47, 0,63, 0,94, 1,25, 1,88, 2,50 mM in DMSO) or DDS-NOH (0,14, 0,19, 0,28, 0,38, 0,56, 0,75, 1,13 1,50 mM in DMSO) over 24, 48 and 72 hrs. DDS and DDS-OH diminished cell viability (MTT assay) in a dose-dependent manner in both cell lines. LDH activity in the incubation medium after a 48-hr exposure to the same DDS or DDS-OH concentrations confirmed MTT results. The anti- oxidants, vitamin C (5 mM), vitamin E (2.5 mM), glutathione (5 mM) and N-acetyl cysteine (4 mM) all attenuated DDS- and DDS-OH-induced cell death in both cell lines. DDS?s deleterious effect on cell viability was exacerbated by the CYP450 inducer, rifampicin (0.1 mM), whereas the CYP450 inhibitor, cimetidine (0.15mM), attenuated this effect in both cell lines. We conclude that DDS citotoxicity involves, at least in part, an oxidative-stress mechanism where CYP450 activity may participate through the formation of its pro-oxidant metabolite, DDS-OH.