Effect of some Indole Derivatives on Xenobiotic Metabolism and Xenobiotic-induced Toxicity in Cultured Rat Liver Slices

Renwick, A.B.; Mistry, H.; Barton, P.T.; Mallet, François; Price, Roger J.; Beamand, J.A.; Lake, Brian G.

doi:10.1016/s0278-6915(99)00026-5

Cited by 30 publications

(12 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both I3C and OME are known to be mixed CYP inducers. I3C elevates CYP1A, CYP2B, and CYP3A activity after 3-day administration to rats (Renwick et al, 1999). Likewise, OME at 300 mg/kg/day elevates CYP1A, CYP2B, and CYP3A activity after 7 days in rats (Masubuchi and Okazaki, 1997).…”

Section: Discussionmentioning

confidence: 90%

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison With Classical Aryl Hydrocarbon Receptor Ligands and Atypical Cyp1a Inducers

Coe

Nelson

Ulrich³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The antiandrogen flutamide (FLU) is used primarily for prostate cancer and is an idiosyncratic hepatotoxicant that sometimes causes severe liver problems. To investigate FLU's overt hepatic effects, especially on inducible drug clearance-related gene networks, FLU's hepatic gene expression profile was examined in female Sprague-Dawley rats using ϳ22,500 oligonucleotide microarrays. Rats were dosed daily for 3 days with FLU at 500, 250, 62.5, 31.3, and 15.6 mg/kg/day, and hepatic RNA was isolated. FLU resulted in the dose-dependent regulation of ϳ350 genes. Employing a gene-response compendium, FLU was compared with three classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene, benzo[a]pyrene, and ␤-naphthoflavone, and four atypical CYP1A inducers, indole-3-carbinol (I3C), omeprazole (OME), chlorpromazine (CPZ), and clotrimazole (CLO). The FLU gene response was comparable with classical AhR ligands across a signature AhR ligand gene set that included CYP1A1 and other members of the AhR gene battery. Dose-related responses of CYP1 genes established a maximum response ceiling and discerned potency differences in atypical inducers. FLU had a sharp down-regulation of c-fos that was comparable with all the compounds except CPZ and CLO. FLU absorption, distribution, metabolism, and excretion (ADME) gene expression analysis revealed that FLU, as well as I3C and OME, induced CYP2B and CYP3A, distinguishing them from the classical AhR ligands. By using a compendium of gene expression profiles, FLU was shown to signal in rats similar to an AhR activator with additional CYP2B and CYP3A effects that most resembled the ADME gene expression pattern of the atypical CYP1A inducers I3C and OME.

show abstract

Section: Discussionmentioning

confidence: 90%

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison With Classical Aryl Hydrocarbon Receptor Ligands and Atypical Cyp1a Inducers

Coe

Nelson

Ulrich³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…3,3Ј-Diindolylmethane (DIM) is one of the major products of indole-3-carbinol that is formed in gastric acid (De Kruif et al, 1991;Staub et al, 2002;Leibelt et al, 2003). DIM induces the expression of phase 1 and phase 2 xenobiotic metabolizing enzymes in the liver and extrahepatic tissues, resulting in the enhanced capacity for the detoxification of carcinogens (Chen et al, 1996;Lake et al, 1998;Renwick et al, 1999;Sanderson et al, 2001;GrossSteinmeyer et al, 2004). Studies clearly showed that DIM administered orally at the dose of 5 mg/kg body weight for 21 days effectively inhibited mammary gland tumor growth by 80% in female Sprague-Dawley rats that were initiated with mammary gland carcinogen, the 7,12-dimethylbenz(a)anthracene (Chen et al, 1998).…”

mentioning

confidence: 99%

3,3′-Diindolylmethane Is a Novel Topoisomerase IIα Catalytic Inhibitor That Induces S-Phase Retardation and Mitotic Delay in Human Hepatoma HepG2 Cells

Gong¹,

Firestone²,

Bjeldanes³

2005

Mol Pharmacol

View full text Add to dashboard Cite

Epidemiological evidence suggests that high consumption of Brassica genus vegetables, such as broccoli, cabbage, and Brussels sprouts, is very effective in reducing the risks of several types of cancers. 3,3Ј-Diindolylmethane (DIM), one of the most abundant and biologically active dietary compounds derived from Brassica genus vegetables, displays remarkable antitumor activity against several experimental tumors. In the present study, we demonstrate for the first time that DIM is a novel catalytic topoisomerase II␣ inhibitor. In supercoiled DNA relaxation assay and kinetoplast DNA decatenation assay, DIM strongly inhibited DNA topoisomerase II␣ and also partially inhibited DNA topoisomerases I and II␤. DIM did not stabilize DNA cleavage complex and did not prevent etoposide-induced DNA cleavage complex formation. Further experiments showed that DIM inhibited topoisomerase II␣-catalyzed ATP hydrolysis, which is a necessary step for the enzyme turnover. In cultured human hepatoma HepG2 cells, DIM blocked DNA synthesis and mitosis in a concentration-dependent manner, which was consistent with the outcome of topoisomerase inhibition in these cell-cycle phases. Our results identified a new mode of action for this intriguing dietary component that might be exploited for therapeutic development.

show abstract

“…It should be noted that other plant products such as avonoids, lignans, curcumin, etc., reduce a atoxin toxicity by modifying the bioactivation process of a atoxin, in which microsomal mixed function oxidase plays a major role [5,6]. In the present experiment, the test compounds reduced the cytotoxicity by interacting directly with a atoxin and converting highly toxic AFB 1 and AFG 1 to less toxic AFB 2 and AFG 2 respectively.…”

Section: Resultsmentioning

confidence: 64%

Chemopreventive Effects of Certain Nutritive Acids on Aflatoxin-induced Cytotoxicity

Verma

Shukla

Mehta³

2001

Journal of Nutritional & Environmental Medicine

View full text Add to dashboard Cite

Many investigators have evaluated the effects of several plant products in modulating in vitro metabolism of a atoxin B 1 (AFB 1 ) by microsomal mixed function oxidase (MFO), thereby reducing its toxicity. However, the importance of these studies is of limited signi cance as MFO is not present in all cells. Our earlier study revealed a concentrationdependent increase in the rate of haemolysis, indicating a atoxin-induced cytotoxicity on red blood cells. It could be due to the direct action of a atoxin on the plasma membrane, as MFO required for bioactivation of AFB 1 is absent in red blood cells. The present study was designed to evaluate the ef cacy of some micronutrients, namely lactic, citric and folic acid, in ameliorating a atoxin-induced cytotoxicity on red blood cells in vitro.A atoxin was obtained by growing Aspergillus parasiticus (NRRL 3240) on sucrose-magnesium sulphate-potassium nitrate-yeast extract (SMKY) liquid medium at 28 6 2°C for 10 days [1]. Extraction and quanti cation of a atoxin were performed using the method of Nabney and Nesbitt [2].Blood samples were taken by venepuncture from healthy adult New Zealand strain rabbits (Oryctolagus cuniculus) and collected in heparinized tubes. A red blood cell (RBC) suspension in normal saline (0.9% NaCl) with a cell density of 2 3 10 4 cells ml 2 1 was prepared [3]. To assess the ef cacy of the test compound (folic acid, citric acid or lactic acid) in amelioration of a atoxin-induced cytotoxicity (haemolysis), 1 ml of the RBC suspension was added to either (a) the test compound (10 l g ml 2 1 ), (b) 2.5 l g ml 2 1 a atoxin [3], or (c) 2.5 l g ml 2 1 a atoxin and 5-100 l g ml 2 1 test compound. The volume of each tube was made up to 2 ml with additional saline in order to have the required concentrations of a atoxin and test compound which were also prepared in normal saline. The tubes were mixed gently and incubated at 37°C for 16 hours with intermittent shaking. Thereafter, the tubes were centrifuged at 1000g for 10 min and the colour density of the supernatant was measured spectrophotometrically at 540 nm. The percentage haemolysis was calculated using the formula: Percentage haemolysis 5Absorbance of the individual tubes Absorbance with 100% haemolysis 3 100.

show abstract

Effect of some Indole Derivatives on Xenobiotic Metabolism and Xenobiotic-induced Toxicity in Cultured Rat Liver Slices

Cited by 30 publications

References 40 publications

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison With Classical Aryl Hydrocarbon Receptor Ligands and Atypical Cyp1a Inducers

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison With Classical Aryl Hydrocarbon Receptor Ligands and Atypical Cyp1a Inducers

3,3′-Diindolylmethane Is a Novel Topoisomerase IIα Catalytic Inhibitor That Induces S-Phase Retardation and Mitotic Delay in Human Hepatoma HepG2 Cells

Chemopreventive Effects of Certain Nutritive Acids on Aflatoxin-induced Cytotoxicity

Contact Info

Product

Resources

About