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.

Assessment of the Antimutagenic Effects of Aqueous Extracts from Herbal Medicines against N-Alkyl-N-nitrosoureas-induced Mutagenicity Using the umu Test

“…The results of the umu test agree with the results of the Ames test and may be more useful with respect to expediting results (23). The umu test applies to screening antimutagenic compounds derived from natural products (24,25). Herbal medicines have been reported for their cancer chemoprevention, however the mechanism is unclear (26).…”

Synthesis of novel psoralen analogues and their in vitro antitumor activity

“…29 The inhibition of CYP1A1 and CYP1A2 has been implicated in the antigenotoxic mechanism of several furocoumarins, such as bergamottin and naringin. 9,30,31 Psoralen and xanthotoxin (8-methoxypsoralen) can be oxidized at the furan ring to form a furanoepoxide that binds to CYP2B1. 32 In addition, xanthotoxin up-regulates CYP1A1 expression.…”

A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats

“…Similarly, the reinforcement of the analgesic effects of corydalis alkaloid in mice by total coumarins of Radix Angelicae dahuricae was related to the improvement in the plasma concentration of dl-THP (substrate of CYP2D6) [ 11 ]. Moreover, previous studies demonstrated that isoimperatorin and imperatorin might be capable of affecting the metabolic activation of procarcinogens by inhibiting human CYP1A1 and CYP1A2 enzymes [ 27 ].…”