Chemopreventive Activity of Porphyrin Derivatives Against 6-Sulfooxymethylbenzo[a]pyrene Mutagenicity

Porphyrins exhibit potent antimutagenic activity in the range of assays in vitro and in vivo. The antimutagenic ‍activities of porphyrin derivatives including phthalocyanines (Pcs) were investigated using 6- ‍sulfooxymethylbenzo[a]pyrene (SMBP) and its proximate metabolite 6-hydroxymethylbenzo[a]pyrene (HMBP) in ‍the Ames assay and hypoxanthine:guanine phosphoribosyl transferase (hprt) point mutation assay in V79 cells. Pcs, ‍irrespective of coordinated metal, showed highly antimutagenic activity against both HMBP and SMBP in the Ames ‍assay. However, their inhibitory effects against HMBP were in general less dramatic than against SMBP. Treatment ‍with chlorophyllin (CHL) and protoporphyrin reduced the mutation frequency to 24.8% and 19.1% of that with ‍SMBP, and 56.5% and 40.7% of that with HMBP, respectively. Hemin, biliverdin and chlorophylls had a lower ‍antimutagenic activity compared with other porphyrin derivatives although they still retained inhibitory capacity ‍against SMBP. The results of the Ames test for SMBP were extended to the mammalian system to confirm the ‍antimutagenicity of porphyrin derivatives. The antimutagenic strength of porphyrin derivatives was in order of ‍hemin, Pcs, CHL and protoporphyrin. Biliverdin, chlorophyll a and chlorophyll b had a little effect against HMBP ‍and SMBP. Among the compounds tested here, hemin had a strong inhibitory effect against SMBP-induced mutation ‍in V79 cells while Pcs were most effective in the microbial system. It is assumed that these discrepancies are partly ‍due to differences in membrane permeability to the chemicals, their metabolisms and chromosomal organization. ‍Furthermore, carcinogen-DNA binding in calf thymus DNA and plasmid was carried out with a series of porphyrin ‍derivatives to understand their protective mechanism. Most of the porphyrin derivatives exhibited inhibitory activity ‍against SMBP with a variety of degrees. A significant reduction of SMBP-mediated DNA damage by Pcs was confirmed ‍on agarose electrophoresis. There was little correlation between the levels of SMBP-DNA adducts and their modulation ‍in mutation frequencies, indicating that porphyrin compounds somehow affect the antioxidant function and the ‍reactivity of SMBP to cellular components.