Cytochrome P450-related differences between rats and mice in the metabolism of benzene, toluene and trichloroethylene in liver microsomes.

In evaluating the risks to humans of exposure to chemicals, the results of studies in rodents are sometimes used as a basis for extrapolation. It is therefore important to elucidate differences in metabolism among species. Differences in cytochrome P450-catalysed oxidation of benzene, toluene and trichloroethylene (TRI) between male Wistar rats and male B6C3F1 mice were investigated by immunoblot and immunoinhibition assays using monoclonal antibodies (MAbs) to cytochrome P450 (CYP1A1/2, CYP2B1/2, CYP2E1 and CYP2C11/6). Immunoblot analysis showed that anti-CYP2B1/2 did not detect any protein in either untreated rat or mouse liver microsomes, whereas with anti-CYP2E1 and/or anti-CYP1A1/2 a clear-cut band was seen more in liver microsomes from mice than from rats. Mouse liver microsomes had a greater monooxidation activity for benzene and TRI than rat liver microsomes; mice also had a higher rate of aromatic hydroxylation of toluene at low substrate concentration, but a low rate of side-chain oxidation when a high concentration of toluene was used. The metabolism of benzene was saturated in mice at around 0.23 mM, but the metabolism of the other two solvents was not saturated in either rats or mice at the low concentrations used. Anti-CYP2E1 inhibited the metabolism of benzene, toluene and TRI in microsomes from mice to a greater extent than in rats, while anti-CYP2C11/6 inhibited their metabolism in rats to a greater extent than in mice; anti-CYP1A1/2 inhibited the metabolism of TRI only in microsomes from mice. These results indicate that (i) male B6C3F1 mice have more CYP2E1 and 1A1/2 than male Wistar rats, whereas rats have more CYP2C11/6 than mice; (ii) rats and mice express CYP2B1/2 but they are not immunochemically detectable; (iii) CYP2E1 and 2C11/6 in both species are responsible for the metabolism of benzene, toluene and TRI, whereas CYP1A1/2 in mice catalyses the oxidation of TRI. The differences in the metabolism of benzene, toluene and TRI in rats and in mice may therefore depend, at least in part, on differences in the distribution of P450 isozymes between the two species.