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.
Highlights
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widely distributed environmental contaminant that possesses multiple species- and tissue-speci c adverse effects such as tumor promotion, teratogenicity, and immune, hepato, cardioand skin toxicity
We previously demonstrated that Peganum harmala extract and its main active constituents, harmine and harmaline decreased the TCDD-mediated induction of Cyp1a1 activity in mouse hepatoma Hepa-1c1c7 cells [8]
The effect of both alkaloids on Cyp1a1 in vivo remains to be examined. erefore, the aim of this study is to examine the effect of harmine and harmaline on TCDDmediated induction of Cyp1a1 in mice livers and lungs
Summary
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widely distributed environmental contaminant that possesses multiple species- and tissue-speci c adverse effects such as tumor promotion, teratogenicity, and immune-, hepato-, cardioand skin toxicity. E adverse effects of TCDD are mainly mediated through binding and activation of ubiquitous transcription factor called aryl hydrocarbon receptor (AhR). It has been demonstrated that the inhibition of AhR activity and its regulated gene, CYP1A1, could result in the prevention of toxic effects caused by the AhR ligands, including carcinogenicity [6]. We previously demonstrated that Peganum harmala extract and its main active constituents, harmine and harmaline decreased the TCDD-mediated induction of Cyp1a1 activity in mouse hepatoma Hepa-1c1c7 cells [8]. We reported that both harmine and harmaline inhibited the TCDD-mediated induction of the carcinogenactivating enzyme, CYP1A1 in human hepatoma HepG2 cells through transcriptional and posttranslational mechanisms [9, 10]. The effect of both alkaloids on Cyp1a1 in vivo remains to be examined. erefore, the aim of this study is to examine the effect of harmine and harmaline on TCDDmediated induction of Cyp1a1 in mice livers and lungs
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