title: Harmine and harmaline downregulate TCDD-induced Cyp1a1 in the livers and lungs of C57BL/6 mice.
abstract: We previously demonstrated that Peganum harmala L. extract and its main active constituents, harmine and harmaline inhibit the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of the carcinogen-activating enzyme, Cyp1a1, in vitro. However, the effect of both alkaloids on Cyp1a1 in vivo has not been investigated. Therefore, the aim of this study is to examine the effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1 in mice livers and lungs. C57BL/6 male mice were distributed into four groups (n = 6). First group received vehicle, while the second group received TCDD (i.p.). The third and fourth groups received either harmine or harmaline (i.p.) × 3 times along with TCDD one time with the mid dose of harmine and harmaline. All mice were sacrificed after 14 h from TCDD injection, and livers and lungs were isolated. The effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1 mRNA, protein, and activity levels was determined using real-time PCR, Western blot analysis, and 7-ethoxyresurofin as a substrate, respectively. Our results showed that harmine and harmaline significantly decreased the TCDD-mediated induction of Cyp1a1 in both the livers and lungs. We concluded that harmine and harmaline are promising candidate to inhibit TCDD-mediated induction of Cyp1a1 in mice hepatic and extrahepatic tissues.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada T6G 2E1.
authors.forename: Mohamed A M
authors.initials: MA
authors.lastname: El Gendy
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004785:Environmental Pollutants; D015971:Gene Expression Regulation, Enzymologic; D006246:Harmaline / Q000494:pharmacology*; D006247:Harmine / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D006247:Harmine; D006246:Harmaline; D019363:Cytochrome P-450 CYP1A1