ABSTRACT:Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-␤ (C/EBP␤), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBP␤ activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBP␤ and/or Nrf2. Immunoblot analysis revealed that M1 Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiol-3-thione] has been studied as a chemopreventive agent for malignancies, such as liver and colorectal cancer (Rao et al., 1993;Kensler, 1997). Comprehensive mechanistic studies indicate that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferases (GSTs) (Bolton et al., 1993;Kensler, 1997). GST induction also accounts for the cytoprotective effect of oltipraz against toxicantinduced injury (Jaitovitch-Groisman et al., 2000;Nelson et al., 2002). A phase IIa randomized chemoprevention trial of oltipraz in residents of Qidong, China, showed that oltipraz might be clinically active as a chemopreventive agent. In the human studies, oltipraz dosage regimens with higher doses and a long-dosing interval seemed to be more efficacious in preventing cancer, as supported by a significant decline in the levels of aflatoxin-albumin adduct in the individuals receiving a higher dose of oltipraz (500 mg/week) (Jacobson et al., 1997;Jackson and Groopman, 1999;Wang et al., 1999).Exposure of experimental animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) Iida et al., 2004) and enhances Nrf2's antioxidant response element (ARE) binding activity (Pietsch et al., 2003). Diminished expression of phase II enzyme genes by oltipraz in the Nrf2 Ϫ/Ϫ mice supports the role of Nrf2 activation in its cancer chemopreventive effects Ramos-Gomez et al., 2001). Molecular signals activated by oxidative stress stimulate translocation of Nrf2 to the nucleus, where it binds and activates the AREs located in the promoter regions of phase II enzyme genes (Moinova and Mulcahy, 1998;Venugopal and Jaiswal, 1998;Huang et al., 2000).Studies from this laboratory showed that oltipraz at clinically relevant concentrations marginally increased the band intensity of Nrf2 ARE binding and thus weakly enhanced the accumulation of Nrf2 in the nucleus. Our results suggested that GSTA2 induction by oltipraz might be mediated by the activation of other transcriptional Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10...

Results indicate that tacrolimus may have a higher risk of inducing liver injury in Korean patients with a history of liver disease and may require close monitoring.

Lamivudine belongs to the set of antiviral agents effective against hepatitis B virus infection. Given case reports on liver injuries after certain antiviral agent treatments, this study examined the effects of lamivudine on alanine aminotransferase (ALT) and total bilirubin (TB) using a medical system database. A total of 1,321 patients taking lamivudine alone or with others were evaluated using laboratory hits in an electronic medical system at Seoul National University Hospital from 2005 through 2011. The patients were grouped according to prior ALT results: G#1, ALT < 40 IU/L; G#2, 40 IU/L ≤ ALT < 120 IU/L; G#3, 120 IU/L ≤ ALT < 240 IU/L; and G#4, ALT ≥ 240 IU/L. In G#1 and G#2 patients, lamivudine or adefovir treatment decreased ALT and TB compared to prior values. In G#3 and G#4 patients with three times the upper limit of normal (ULN) ≤ ALT < 15 times the ULN, both ALT and TB were decreased after treatment with lamivudine alone, or adefovir following lamivudine therapy, indicating that lamivudine therapy ameliorated liver functions. However, in G#4 patients who experienced severely advanced hepatitis (ALT ≥ 15 times the ULN, or ≥ 600 IU/L), lamivudine augmented TBmax (6.3→13.3 mg/dL) despite a slight improvement in ALT (839→783 IU/L), indicative of exacerbation of bilirubinemia. Patients who used adefovir after lamivudine also showed a high incidence of hyperbilirubinemia when they experienced severely advanced hepatitis. Treatment with adefovir alone did not show the effect. In conclusion, lamivudine may increase the risk of hyperbilirubinemia in patients with severely advanced hepatitis, implying that caution should be exercised when using lamivudine therapy in certain patient populations.