title: Antigenotoxic activity of naturally occurring furanocoumarins.
abstract: This study was designed to investigate the antigenotoxic effects of a series of naturally occurring furanocoumarins (NOFs) including isoimperatorin, imperatorin, (+)-oxypeucedanin, (+)-byakangelicol, and (+)-byakangelicine on antigenotoxic activities against genotoxicity induced by carcinogens [furylfuramide and N-methyl-N'-nitro-N-nitrosoguanidine], and procarcinogens 2-[2-(acetylamino)-4-amino-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-4) and 2-amino-3,4-dimethyl-3H-imidazo-[4,5-f] quinoline (MeIQ)] to genotoxic metabolites catalyzed by rat S9 or rat and human recombinant cytochrome P450 (CYP) 1As by using the umu test based on SOS response. Five different NOFs, which were found in the human diets, strongly inhibited the umuC induction by procarcinogens, but did not be affected by carcinogens. Notably, isoimperatorin and (+)-byakangelicol were found to be potent inhibitors on the metabolic activation of PBTA-4 and MeIQ to genotoxic metabolites catalyzed by rat and human CYP1A1, or rat and human CYP1A2, respectively. In addition, to elucidate the mechanism of their antigenotoxic effects against procarcinogens, the effects of NOFs on rat and human CYP1A1- or rat and human CYP1A2-related enzyme activities of 7-ethoxyresorufin-O-deethylase (EROD) were also investigated. Reduction of the EROD activities by some of the NOFs with IC(50) values of 0.23-20.64 μM was found to be due to strong inhibition of CYP1A1 and CYP1A2 dependent monooxygenases. Furthermore, the mechanism of inhibitions by NOFs on human CYP1A1 and CYP1A2 was analyzed by means of Dixon plots plus Cornish-Bowden plots. The kinetic studies of inhibition types revealed that these compounds inhibited the human CYP1A1 and CYP1A2 a variety of modes rather than by a uniform one. Moreover, experiments with a two-stage incubation indicated that NOFs, except for imperatorin, inhibited human CYP1A1 in a mechanism-based manner, but directly inhibited human CYP1A2. This data suggest that certain NOFs, to which humans are exposed in the diet, may be capable of affecting the metabolic activation of procarcinogens due to inhibitions of CYP1A1 and CYP1A2 enzymes.
authors.affiliation: Department of Applied Chemistry, Kinki University, Kowakae, Higashiosaka-Shi, Osaka, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Marumoto
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Oda
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Miyazawa
mesh_terms: D000818:Animals; D016587:Antimutagenic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics; D002274:Carcinogens, Environmental / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004249:DNA Damage / Q000187:drug effects*; D011564:Furocoumarins / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D009153:Mutagens / Q000633:toxicity; D051381:Rats; D013014:SOS Response, Genetics / Q000187:drug effects*; D012486:Salmonella typhimurium / Q000235:genetics
chemical_list: D016587:Antimutagenic Agents; D002274:Carcinogens, Environmental; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D011564:Furocoumarins; D009153:Mutagens; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human