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Harmine and harmaline downregulate TCDD-induced Cyp1a1 in the livers and lungs of C57BL/6 mice
Mohamed A M El Gendy1, Ayman O S El-Kadi
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada T6G 2E1.
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.
Insights
Peganum harmala alkaloids, harmine and harmaline, were investigated for their in vivo effects. These compounds significantly inhibited the induction of the carcinogen-activating enzyme Cyp1a1 in mice livers and lungs following TCDD exposure.
Area of Science:
- Pharmacology and Toxicology
- Natural Product Chemistry
- Carcinogenesis Research
Background:
- Peganum harmala L. extracts, harmine, and harmaline inhibit Cyp1a1 induction in vitro.
- The in vivo effects of these alkaloids on Cyp1a1 induction, particularly concerning TCDD exposure, remain uninvestigated.
- Cyp1a1 is a key enzyme in the activation of carcinogens like TCDD.
Purpose of the Study:
- To investigate the in vivo effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1.
- To assess the impact on both hepatic and extrahepatic tissues, specifically livers and lungs in mice.
Main Methods:
- C57BL/6 male mice were administered vehicle, TCDD, or TCDD combined with harmine or harmaline.
- Cyp1a1 mRNA, protein, and activity levels were quantified in liver and lung tissues.
- Techniques included real-time PCR, Western blot analysis, and enzyme activity assays using 7-ethoxyresorufin.
Main Results:
- Harmine and harmaline significantly reduced TCDD-induced Cyp1a1 mRNA, protein, and activity in mouse livers.
- A similar significant decrease in TCDD-mediated Cyp1a1 induction was observed in mouse lungs.
- Both alkaloids demonstrated efficacy in inhibiting Cyp1a1 in hepatic and extrahepatic tissues.
Conclusions:
- Harmine and harmaline effectively inhibit TCDD-induced Cyp1a1 in vivo in mice.
- These alkaloids show promise as potential therapeutic agents to counteract TCDD toxicity.
- Further research into their mechanisms and therapeutic applications is warranted.
