1995 Volume 10 Issue supplement Pages 162-165
An attempt was made to elucidate the mechanism for accumulation and retention of imidazole derivatives in the connective tissue by using the radio-labeled imidazoles, [2-14C]imidazole and 2-methyl[2-14C]imidazole. Distribution studies in rats revealed that these compounds were retained in the connective tissue, probably with the irreversible binding to elastin. The binding formation could not be ascribed to spontaneously occurring noncatalytic reaction or to P450-mediated activation. Although pretreatment of rats with a xanthine oxidase (XOD) inhibitor allopurinol (ALP) resulted in decreased levels of tissue-bound aortic radioactivity from the imidazoles, in vitro binding to aortic tissue was scarcely observed in the presence of purified XOD. On the other hand, certain oxidation products generated in copper(II)/ascorbate system (Cu/VC) were shown to bind firmly to aortic tissue. Under this condition, addition of ALP decreased the tissue binding. ALP can form the complex with both Cu and VC in vitro as reported previously. In view of this information, in vivo ALP-treatment effect described above may be well explained by inhibition of Cu/VC-catalyzed oxidation. Moreover, from LC/MS/MS analysis of the oxidation products in Cu/VC, it was conceivable that imidazolones bind to α-aminoadipic-δ-semialdehyde (allysine) residues in elastin or collagen. Based on these findings, the nonenzymatic oxidation process is considered to be one of the major causative elements in the metabolic activation of imidazole derivatives. Further studies using LEC rat, an animal model of Wilson's disease, are currently being carried out.
