In vivo induction of phase II detoxifying enzymes, glutathione transferase and quinone reductase by citrus triterpenoids

Abstract

BackgroundSeveral cell culture and animal studies demonstrated that citrus bioactive compounds have protective effects against certain types of cancer. Among several classes of citrus bioactive compounds, limonoids were reported to prevent different types of cancer. Furthermore, the structures of citrus limonoids were reported to influence the activity of phase II detoxifying enzymes. The purpose of the study was to evaluate how variations in the structures of citrus limonoids (namely nomilin, deacetyl nomilin, and isoobacunoic acid) and a mixture of limonoids would influence phase II enzyme activity in excised tissues from a mouse model.MethodsIn the current study, defatted sour orange seed powder was extracted with ethyl acetate and subjected to silica gel chromatography. The HPLC, NMR and mass spectra were used to elucidate the purity and structure of compounds. Female A/J mice were treated with three limonoids and a mixture in order to evaluate their effect on phase II enzymes in four different tissues. Assays for glutathione S-transferase and NAD(P)H: quinone reductase (QR) were used to evaluate induction of phase II enzymatic activity.ResultsThe highest induction of GST against 1-chloro-2,4-dinitrobenzene (CDNB) was observed in stomach (whole), 58% by nomilin, followed by 25% isoobacunoic acid and 19% deacetyl nomilin. Deacetyl nomilin in intestine (small) as well as liver significantly reduced GST activity against CDNB. Additionally isoobacunoic acid and the limonoid mixture in liver demonstrated a significant reduction of GST activity against CDNB. Nomilin significantly induced GST activity against 4-nitroquinoline 1-oxide (4NQO), intestine (280%) and stomach (75%) while deacetyl nomilin showed significant induction only in intestine (73%). Induction of GST activity was also observed in intestine (93%) and stomach (45%) treated with the limonoid mixture. Finally, a significant induction of NAD(P)H: quinone reductase (QR) activity was observed by the limonoid mixture in stomach (200%). In addition, the deacetyl nomilin treatment group displayed an increase in QR activity in liver (183%) and intestine (22%).ConclusionThe results of the present study suggests that, dietary intake of citrus limonoids may provide a protective effect against the onset of various cancers by inducing the activity of certain phase II detoxifying enzymes in specific organs.

The Chemistry and Pharmacology of Citrus Limonoids

“…Following their studies in vitro [49], Perez et al also evaluated how CLs 2, deacetylnomilin (4), isoobacunoic acid (9), and a mixture of limonoids would influence phase II enzyme activity in female A/J mice [70]. The highest induction of GST against 1-chloro-2,4-dinitrobenzene (CDNB) was observed in stomach (whole), with the most active CL being 2 (58%), followed by 9 (25%), and 4 (19%).…”

“…The unbalanced solubility profile of the latter may explain the relatively low number of studies on their respective biological activities which are hampered by difficult isolation from natural sources and poor pharmacokinetics. Analgesic [45], anticancer [46][47][48][49][50][51][52][53][54][55][56][57][58][59], anti-inflammatory [45,[60][61][62], antibacterial [63,64], antioxidant [4,65,66], antiviral [67], larvicidal [68,69] Anticancer [46,47,58,59,70], anti-hyperglycemic [71], anti-inflammatory [25,62], antioxidant [4,65,66], antiviral [67], larvicidal [68,69] …”

Effects of Bu-Zhong-Yi-Qi-Tang on hepatic drug-metabolizing enzymes and plasma tolbutamide concentration in rats

“…GST not only acts as a Phase II detoxifying enzyme but also catalyzes the reaction of glutathione with electrophiles, resulting in the elimination of potentially carcinogenic chemicals (Hayes and Pulford, 1995). Induction GST was found when administrated with Panax ginseng (Gum et al, 2007;Lee et al, 2008) and Citrus reticulate (Perez et al, 2010). Induction UGT was found with administrated of flavonoids of Citrus fruits (Xie et al, 2007).…”

Cancer preventive effects of a specific probiotic fermented milk containing Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2 on male F344 rats treated with 1,2-dimethylhydrazine

“…When an induction of GST activity is observed in an organism, it usually correlates with improved detoxification potential against harmful compounds (Perez et al, 2010). In fact, an induction of GST expression by dietary nutrients or drugs enhances the toxicological defence of normal colon tissue, thus reducing their exposure to carcinogens.…”