Inhibition of epidermal xenobiotic metabolism in SENCAR mice by naturally occurring plant phenols.
Naturally occurring plant phenols such as tannic acid, quercetin, myricetin, and anthraflavic acid have been shown to inhibit the mutagenicity of several bay-region diol-epoxides of polycyclic aromatic hydrocarbons including benzo(a)pyrene (BP). The present study was designed to determine whether these plant phenols can alter epidermal cytochrome P-450-dependent monooxygenases in SENCAR mice. In vitro addition of these plant phenols to epidermal microsomal preparations inhibited aryl hydrocarbon hydroxylase (AHH) activity in a concentration-dependent manner. The 50% inhibitory concentrations for tannic acid, myricetin, quercetin, and anthraflavic acid ranged from 4.4 X 10(-5) M to 12.4 X 10(-5) M in microsomes prepared from control and 3-methylcholanthrene-pretreated animals. Of the plant phenols studied tannic acid was found to be the most potent inhibitor of epidermal AHH activity. Tannic acid, quercetin, myricetin, and anthraflavic acid exhibited a mixed type of inhibitory effect with Ki values of 81, 63, 135, and 165 microM, respectively. In vitro addition of these plant phenols (240 microM) to the incubation mixture prepared from control and 3-methylcholanthrene-treated animals resulted in varying degrees of inhibition of epidermal microsomal AHH (57-92%), ethoxycoumarin O-deethylase (19-58%), and ethoxyresorufin O-deethylase (33-85%) activities. High pressure liquid chromatographic analysis of the organic solvent-soluble metabolites of BP produced by epidermal microsomes indicated a substantial decrease in the formation of BP-diols (23-67%) and BP-phenols (29-57%) by each of the plant phenols. The formation of BP-7,8-diol was substantially inhibited (29-52%) by each of the plant phenols. Further in vivo studies showed that a single topical application of tannic acid, quercetin, and myricetin greatly diminished epidermal AHH (53-65%), ethoxycoumarin O-deethylase (30-68%), and ethoxyresorufin O-deethylase (66-97%) activities whereas anthraflavic acid was ineffective in this regard even when repeatedly applied. Our results indicate that plant phenols have substantial though variable inhibitory effects on epidermal monooxygenase activities and BP metabolism suggesting that these compounds may be capable of inhibiting the carcinogenic effects of polycyclic aromatic hydrocarbons in the skin.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D019363:Cytochrome P-450 CYP1A1; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010105:Oxygenases / Q000037:antagonists & inhibitors; D010636:Phenols / Q000494:pharmacology*; D010944:Plants; D011794:Quercetin / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D005419:Flavonoids; D047348:Hydrolyzable Tannins; D010636:Phenols; C040015:myricetin; D011794:Quercetin; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C034889:2,6-dihydroxyanthraquinone