TY - JOUR
AU - Hollenberg, Paul F.
AB - Ellagic acid (EA), a naturally occurring plant polyphenol possesses broadchemoprotective properties. Dietary EA has been shown to reduce the incidence ofN-2-fluorenyl acetamide-induced hepatocarcinogenesis inrats and N-nitrosomethylbenzylamine (NMBA)-induced ratesophageal tumors. In this study changes in the expression and activities ofspecific rat hepatic and esophageal mucosal cytochromes P450 (P450) and phase IIenzymes following dietary EA treatment were investigated. Liver and esophagealmucosal microsomes and cytosol were prepared from three groups of Fisher 344rats which were fed an AIN-76 diet containing no EA or 0.4 or 4.0 g/kg EAfor 23 days. In the liver total P450 content decreased by up to 25% andP450 2E1-catalyzed p-nitrophenol hydroxylation decreased by15%. No changes were observed in P450 1A1, 2B1 or 3A1/2 expressionor activities or cytochrome b5activity. P450 reductase activitydecreased by up to 28%. Microsomal epoxide hydrolase (mEH) expressiondecreased by up to 85% after EA treatment, but mEH activities did notchange. The hepatic phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone reductase (NAD(P)H: QR) and UDP glucuronosyltransferase (UDPGT)activities increased by up to 26, 17 and 75% respectively. Assays forspecific forms of GST indicated marked increases in the activities of isozymes2-2(190%), 4-4 (150%) and 5-5 (82%). In the rat esophagealmucosa only P450 1A1 could be detected by Western blot analysis andandrostendione was the only P450 metabolite of testosterone detectable. However,there were no differences in the expression of P450 1A1, the formation ofandrostendione or NAD(P)H: QR activities between controland EA-fed rats in theesophagus. Although there was no significant decrease in overall GST activity,as measured with 1-chloro-2, 4-dinitrobenzene (CDNB), there was a significantdecrease in the activity of the 2-2 isozyme (66% of control). Invitro incubations showed that EA at a concentration of 100μM inhibited P450 2E1, 1A1 and 2B1 activities by 87, 55 and 18%respectively, but did not affect 3A1/2 activity. Using standardsteady-state kinetic analyses, EA was shown to be a potent non-competitiveinhibitor of both liver microsomal ethoxyresorufin O-deethylaseand p-nitrophenol hydroxylase activities, with apparentK1 values of ∼55 and 14 μMrespectively. In conclusion, these results demonstrate that EA causes a decreasein total hepatic P450 with a significant effect on hepatic P450 2E1, increasessome hepatic phase II enzyme activities (GST, NAD(P)H: QR and UDPGT) anddecreases hepatic mEH expression. It also inhibits the catalytic activity ofsome P450 isozymes in vitro. Thus the chemoprotective effect ofEA against various chemically induced cancers may involve decreases in the ratesof metabolism of these carcinogens by phase I enzymes, due to both directinhibition of catalytic activity and modulation of gene expression, in additionto effects on the expression of phase II enzymes, thereby enhancing the abilityof the target tissues to detoxify the reactive intermediates.
TI - The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes
JF - Carcinogenesis
DO - 10.1093/carcin/17.4.821
DA - 1996-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/the-effects-of-dietary-ellagic-acid-on-rat-hepatic-and-esophageal-0sXoT6bZi5
SP - 821
EP - 828
VL - 17
IS - 4
DP - DeepDyve
ER -