CHARACTERIZATION OF THE TOXIC METABOLITE(S) OF NAPHTHALENE

The toxicity of naphthalene and its metabolites has been investigated in vitro. Both naphthalene and its metabolite l-naphthol were bioactiv ated by human hepatic microsomes to metabolite(s) which were toxic to mononuclear leucocytes (MNL). However, l-naphthol was more cytotoxic t han naphthalene (49.8 +/- 13.9% vs. 19.0 +/- 10.0% cell death; P < 0.0 1), indicating that the toxicity of naphthalene is dependent on the bi oactivation of l-naphthol. CYP2El-induced rat liver microsomes increas ed metabolism of naphthalene by 13% compared to control microsomes wit h a concomitant increase in both l-naphthol and dihydrodiol formation. The cytotoxicity of naphthalene but not of l-naphthol was increased b y CYP2E1 induction, indicating that separate enzymes are involved in t he bioactivation of l-naphthol. The metabolites of l-naphthol, 1,2-nap hthoquinone (51.4 +/- 6.6% cell death) and 1,e-naphthoquinone (49.1 +/ - 3.4% cell death) were directly toxic to MNL and depleted glutathione to 1.0% of the control levels. Both quinones were also genotoxic to h uman lymphocytes. In contrast, the primary metabolite of naphthalene, the 1,2-epoxide (0-100 mu M) was neither cytotoxic nor genotoxic, and did not deplete glutathione. In conclusion, our data suggests that the cytotoxicity and genotoxicity of naphthalene is associated with the f ormation of quinones from I-naphthol rather than naphthalene-l,2-epoxi de.