Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide

Abstract

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261-269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male SpragueDawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F 1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 µmol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.

Anti-Inflammatory Activity of Capsaicin and Dihydrocapsaicin through Heme Oxygenase-1 Induction in Raw264.7 Macrophages

“…CAP and structurally related vanilloid analogues, such as curcumin and zingerone, possess antioxidant activity (Surh et al . ; Rosa et al . ; Shin et al .…”

“…Thus, this concentration (200 μM) was chosen to determine the effect of CAP and DHC on NO production by treatment with an HO-1 inhibitor. CAP and structurally related vanilloid analogues, such as curcumin and zingerone, possess antioxidant activity (Surh et al 1998;Rosa et al 2002;Shin et al 2005). It has also been reported that various natural compounds including vanilloids modulate the induction of HO-1 in tissue culture models (Joung et al 2007;Hsu et al 2008).…”

Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice

“…AFP is specific biomarker of hepatocellular carcinoma and synthesis in the fetal stage of germ cells. Earlier study reported that active metabolite; vinyl carbamate-induced hepatic lesions and metastasis (Surh et al, 1998 ). Patients with primary lung carcinoma and testicular metastasis showed significant elevation of AFP (Yamagata et al, 2004 ).…”

Development of Thiazolidinone-Based Pyrazine Derivatives: Synthesis, Molecular Docking Simulation, and Bioevaluation for Anti-Alzheimer and Antibacterial Activities

“…Nature is hepatoprotective and rigorous. However, certain pyrazines are toxic, such as those that impede cytochrome P450 synthesis [27] or activate liver microsomal explode hydrolase, an enzyme used in mammalian detoxifcation [28,29]. As pyrazine and thiazolidnone moieties are biologically active [30][31][32][33][34][35][36][37][38][39][40], herein the current work, Ncontaining derivatives such as pyrazine-based thiazolidinone derivatives were synthesized and tested for biological activity to analyze their substantial impacts on Alzheimer's disease.…”