Previously it was shown that methylenedioxybenzenes (MDBs), particularly isosafrole, were highly effective at preventing CCl 4-induced liver necrosis in vivo (Z.S. Zhao, P.J. O'Brien, The prevention of CCl 4-induced liver necrosis in mice by naturally occurring methylenedioxybenzenes, Toxicol. Appl. Pharmacol., 140 (1996) 411–421), probably as a result of forming metabolic intermediate complexes with cytochrome P450. In the following it was shown that pretreatment of mice with isosafrole also completely prevented ferric nitrilotriacetate (FeNTA)-induced renal necrosis and lipid peroxidation, even though metabolic activation by cytochrome P450 is not involved. The naturally occurring or synthetic MDBs that prevented CCl 4 hepatotoxicity also prevented hepatocyte lipid peroxidation induced by FeNTA, but other cytochrome P450 inhibitors were ineffective. These compounds, in decreasing order of antioxidant effectiveness, were sesamol, 4- t-butyl-methylenedioxybenzene, isosafrole, piperonyl butoxide and 4-bromo-methylenedioxybenzene and safrole, whereas, benzodioxole, 3,4-(methylenedioxy)-toluene and 1,2-(methylenedioxy)-4-nitrobenzene were ineffective. Pre-incubating the hepatocytes with P450 inhibitors decreased the protective effects of isosafrole, suggesting that the catecholic metabolites of MDBs were responsible for the antioxidant activity. A greater inhibition of FeNTA-induced lipid peroxidation by catecholic metabolites was observed. Since cytochrome P450 did not participate in FeNTA-induced hepatocyte or microsomal lipid peroxidation, it is likely that the antioxidant properties of MDBs or their catecholic metabolites also contribute to their in vivo protection against CCl 4 or FeNTA-induced hepato- or nephrotoxicity.