Previously it was shown that
methylenedioxybenzenes (MDBs), particularly
isosafrole, were highly effective at preventing CCl4-induced liver
necrosis in vivo (Z.S. Zhao, P.J. O'Brien, The prevention of CCl4-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 CCl4 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 CCl4 or FeNTA-induced hepato- or nephrotoxicity.