Inhibitory effect of hemin on the mutagenicity of electrophilic sulfuric acid ester of 6-hydroxymethylbenzo[a]pyrene

Abstract

Porphyrin compounds have been known to inhibit mutations induced by several chemical carcinogens. The chemopreventive activity of porphyrin compounds were monitored by using 6-sulfooxymethylbenzo[a]pyrene (SMBP), which is an ultimate metabolite of benzo[a]pyrene. The porphyrin compounds were quite effective in reducing both cytotoxicity and mutagenicity for SMBP at the concentration of 10㎛. Their protective effect against the mutagenicity of SMBP was in the following decreasing order: hemin, chlorophyllin, biliverdin, protoporphyrin, chlorophyll b and chlorophyll a. The inhibitory patterns of hemin for SMBP was also confirmed in S. typhimurium strains TA98 and 100. Mutation frequency caused by SMBP was diminished almost to control level at 5 nmol hemin concentration. The inhibitory effects of hemin against the assault of SMBP in V79 cells was found to related to the reduced cellular uptake of SMBP and further the remarkably lowered DNA adducts. Furthermore, hemin suppresed the hepatic cytosol and PAPS-mediated covalent binding of HMBP to DNA, possibly through inhibition of hydroxysteroid sulfotransferase, which is responsible for the formation of sulfuric acid ester from the parent alcohol. The complex formation of hemin with SMBP was confirmed by solvent extraction and the hydrolysis product identified by reverse-phase HPLC. Such a complex formation will lead to decreased cellular uptake of SMBP. The inhibition of enzyme and the inactivation of sulfur acid ester metabolite are possible chemopreventive mechanisms of porphyrin compound against SMBP.