Abstract
Dioxins are widespread environmental contaminants that have been linked with a variety of deleterious effects on human health including increased cancer rates. The detrimental effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one of the most common environmental dioxins) are mediated via the aryl hydrocarbon receptor (AhR). AhR is a transcription factor that regulates the expression of the carcinogen-activating enzyme, cytochrome P450 1a1 (Cyp1a1). In the present study, we examined the ability of the methanolic extract of Peganum harmala L. (Zygophyllaceae) fruiting tops to affect TCDD-activated AhR-mediated signal transduction in mouse hepatoma Hepa 1c1c7 cells. Our results showed that Peganum harmala extract significantly inhibited the TCDD-mediated induction of Cyp1a1 at mRNA, protein, and activity levels. A similar pattern of inhibition at the catalytic activity level was observed with the other AhR ligands tested. The ability of the extract to inhibit Cyp1a1 was strongly correlated with its ability to inhibit AhR-dependent luciferase activity and electrophoretic mobility shift assays. Harmine and harmaline were found to be the dominant components of the plant extract with a relative abundance of 7 and 4.85 % (w/w), respectively. In addition, both of the active alkaloids showed an inhibitory effect on TCDD-induced Cyp1a1 activity level. We concluded that Peganum harmala L. can interfere with AhR ligands-mediated effects.
Key words
aryl hydrocarbon receptor - cytochrome P450 1a1 -
Peganum harmala L.
- Zygophyllaceae - harmine - harmaline
References
-
1
Belpomme D, Irigaray P, Hardell L, Clapp R, Montagnier L, Epstein S, Sasco A J.
The multitude and diversity of environmental carcinogens.
Environ Res.
2007;
105
414-429
-
2
Mandal P K.
Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology.
J Comp Physiol [B].
2005;
175
221-230
-
3
Puga A, Ma C, Marlowe J L.
The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways.
Biochem Pharmacol.
2009;
77
713-722
-
4
Dertinger S D, Nazarenko D A, Silverstone A E, Gasiewicz T A.
Aryl hydrocarbon receptor signaling plays a significant role in mediating benzo[a]pyrene- and cigarette smoke condensate-induced cytogenetic damage in vivo.
Carcinogenesis.
2001;
22
171-177
-
5
Shimada T, Fujii-Kuriyama Y.
Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1.
Cancer Sci.
2004;
95
1-6
-
6
Nebert D W, Dalton T P, Okey A B, Gonzalez F J.
Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.
J Biol Chem.
2004;
279
23847-23850
-
7
Shah P P, Saurabh K, Pant M C, Mathur N, Parmar D.
Evidence for increased cytochrome P450 1A1 expression in blood lymphocytes of lung cancer patients.
Mutat Res.
2009;
670
74-78
-
8
Slattery M L, Samowtiz W, Ma K, Murtaugh M, Sweeney C, Levin T R, Neuhausen S.
Cyp1a1, cigarette smoking, and colon and rectal cancer.
Am J Epidemiol.
2004;
160
842-852
-
9
Hu Z, Yang X, Ho P C, Chan S Y, Heng P W, Chan E, Duan W, Koh H L, Zhou S.
Herb-drug interactions: a literature review.
Drugs.
2005;
65
1239-1282
-
10
Wiseman L R, Spencer C M.
Paclitaxel. An update of its use in the treatment of metastatic breast cancer and ovarian and other gynaecological cancers.
Drugs Aging.
1998;
12
305-334
-
11
Wang H K.
Plant-derived anticancer agents currently in clinical use or in clinical trials.
I Drugs.
1998;
1
92-102
-
12
Whitlock J A, Krailo M, Reid J M, Ruben S L, Ames M M, Owen W, Reaman G.
Phase I clinical and pharmacokinetic study of flavopiridol in children with refractory solid tumors: a Children's Oncology Group Study.
J Clin Oncol.
2005;
23
9179-9186
-
13
Amakura Y, Tsutsumi T, Nakamura M, Kitagawa H, Fujino J, Sasaki K, Yoshida T, Toyoda M.
Preliminary screening of the inhibitory effect of food extracts on activation of the aryl hydrocarbon receptor induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Biol Pharm Bull.
2002;
25
272-274
-
14
Lamchouri F, Settaf A, Cherrah Y, Zemzami M, Lyoussi B, Zaid A, Atif N, Hassar M.
Antitumour principles from Peganum harmala seeds.
Therapie.
1999;
54
753-758
-
15 Bellakhdar J. La pharmacopee marocaine traditionnelle. Medecine arabe ancienne et savoirs populaires. Paris; Ibis Press 1997: 529-530
-
16
Tahraoui A, El-Hilaly J, Israili Z H, Lyoussi B.
Ethnopharmacological survey of plants used in the traditional treatment of hypertension and diabetes in south-eastern Morocco (Errachidia province).
J Ethnopharmacol.
2007;
110
105-117
-
17
Monsef H R, Ghobadi A, Iranshahi M, Abdollahi M.
Antinociceptive effects of Peganum harmala L. alkaloid extract on mouse formalin test.
J Pharm Pharm Sci.
2004;
7
65-69
-
18
Berrougui H, Isabelle M, Cloutier M, Hmamouchi M, Khalil A.
Protective effects of Peganum harmala L. extract, harmine and harmaline against human low-density lipoprotein oxidation.
J Pharm Pharmacol.
2006;
58
967-974
-
19
El Gendy M A, El-Kadi A O.
Peganum harmala L. differentially modulates cytochrome P450 gene expression in human hepatoma HepG2 cells.
Drug Metab Lett.
2009;
, in press
-
20
Anwar-Mohamed A, El-Kadi A O.
Down-regulation of the carcinogen-metabolizing enzyme cytochrome P450 1a1 by vanadium.
Drug Metab Dispos.
2008;
36
1819-1827
-
21
Korashy H M, El-Kadi A O.
Regulatory mechanisms modulating the expression of cytochrome P450 1A1 gene by heavy metals.
Toxicol Sci.
2005;
88
39-51
-
22
Lorenzen A, Kennedy S W.
A fluorescence-based protein assay for use with a microplate reader.
Anal Biochem.
1993;
214
346-348
-
23
Elbekai R H, El-Kadi A O.
Transcriptional activation and posttranscriptional modification of Cyp1a1 by arsenite, cadmium, and chromium.
Toxicol Lett.
2007;
172
106-119
-
24
Wong B Y, Lau B H, Yamasaki T, Teel R W.
Modulation of cytochrome P-450IA1-mediated mutagenicity, DNA binding and metabolism of benzo[a]pyrene by Chinese medicinal herbs.
Cancer Lett.
1993;
68
75-82
-
25
Chun Y J, Kim M Y, Guengerich F P.
Resveratrol is a selective human cytochrome P450 1A1 inhibitor.
Biochem Biophys Res Commun.
1999;
262
20-24
-
26
Lee J E, Safe S.
Involvement of a post-transcriptional mechanism in the inhibition of Cyp1a1 expression by resveratrol in breast cancer cells.
Biochem Pharmacol.
2001;
62
1113-1124
-
27
Sobhani A M, Ebrahimi S A, Mahmoudian M.
An in vitro evaluation of human DNA topoisomerase I inhibition by Peganum harmala L. seeds extract and its beta-carboline alkaloids.
J Pharm Pharm Sci.
2002;
5
19-23
-
28
Li Y, Liang F, Jiang W, Yu F, Cao R, Ma Q, Dai X, Jiang J, Wang Y, Si S.
DH334, a beta-carboline anti-cancer drug, inhibits the CDK activity of budding yeast.
Cancer Biol Ther.
2007;
6
1193-1199
-
29
Pulpati H, Biradar Y S, Rajani M.
High-performance thin-layer chromatography densitometric method for the quantification of harmine, harmaline, vasicine, and vasicinone in Peganum harmala.
J AOAC Int.
2008;
91
1179-1185
-
30
al-Allaf T A, Khuzaie R F, Rashan L J, Halaseh W F.
Cytotoxic activity against a series of tumour cell lines of dimethyltin dichloride complexes with various donor ligands.
Boll Chim Farm.
1999;
138
267-271
-
31
Yu A M, Idle J R, Krausz K W, Kupfer A, Gonzalez F J.
Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmine.
J Pharmacol Exp Ther.
2003;
305
315-322
Dr. Ayman O. S. El-Kadi
Faculty of Pharmacy & Pharmaceutical Sciences
University of Alberta
3126 Dentistry/Pharmacy Centre
Edmonton, AB T6G 2N8
Canada
Phone: + 1 78 04 92 30 71
Fax: + 1 78 04 92 12 17
Email: aelkadi@pharmacy.ualberta.ca
