The relationship between the binding of 2-n-alkylbenzimidazoles to rat hepatic microsomal cytochrome P-450 and the inhibition of monooxygenation.

The binding of a homologous series of 2-n-alkylbenzimidazoles to rat hepatic microsomal cytochrome P-450 has been examined. Type I, Type RI and mixed Type I/RI spectra were observed with control, phenobarbitone or 20-methylcholanthrene-induced microsomal preparations. In general short chain (C1-C4) substituted compounds elicited Type RI spectra, whereas C5-C9 substituted benzimidazoles gave rise to Type RI/I or Type I spectra. The type of binding spectrum observed was dependent upon the substrate concentration, the source of microsomes and the length of the substituent alkyl chain. As the lipophilic character of the substituent was increased a corresponding increase in Type I nature was noted. However, an optimal chain length of C7-C8 carbon atoms was observed for Type I binding; compounds with longer side chains showed a decreased affinity for the Type I site. The apparent spectral binding constants (Ks values) for the Type I site (but not the Type RI site) were closely associated with the Ki and I50 values for the inhibition of cytochrome P-450-dependent monooxygenation. From their inhibition properties it seems that even the short chain (C1-C4) substituted benzimidazoles also bind toi the Type I site and thus compete for the substrate binding site of cytochrome P-450.