Tacrolimus therapy causes hepatotoxicity in patients with a history of liver disease.

OBJECTIVE: Tacrolimus is known to have little hepatotoxicity. Nevertheless, a few case studies have shown liver toxicities of tacrolimus, particularly in patients on multiple medications. This study is a retrospective data analysis on the potential of tacrolimus hepatotoxicity. METHODS: A data analysis was conducted on the electronic medical records (EMRs) of 2,462 Korean patients taking tacrolimus or cyclosporine from 2002 through to 2008. Alanine aminotransferase (ALT) and total bilirubin level (TBL) were also monitored. The maximum ALT, time to reach ALTmax (TALTmax), and TBL(ALTmax) were compared between the tacrolimus and cyclosporine groups. Other possible factors that may aggravate liver function were also investigated. RESULTS: ALTmax and TBL(ALTmax) were higher in the tacrolimus group compared to the cyclosporine group (i.e., 50 IU/L vs. 41 IU/L and 1 mg/dL vs. 0.9 mg/dL, respectively), and TALTmax was shorter (i.e., 101 days vs. 142 days) in the tacrolimus group. In addition, the frequency of ALTmax > 3x upper limit of normal (ULN) (i.e., ALTmax > 120) was significantly increased in the tacrolimus group compared to the cyclosporine group (30% vs. 21%). The severity of tacrolimusinduced liver damage was greater in patients with history of liver disease, as indicated by > two-fold greater ALTmax than that of cyclosporine (i.e., 153 IU/L vs. 65 IU/L). Moreover, the ALTmax was significantly lowered by switching from tacrolimus to cyclosporine in patients with a history of liver disease. In patients with preexisting renal disease, neither tacrolimus nor cyclosporine showed any effect on ALTmax. CONCLUSION: 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 Therapy Exacerbates Bilirubinemia in Patients Underlying Severely Advanced Hepatitis.

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.

Differential effects of the oxidized metabolites of oltipraz on the activation of CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 for GSTA2 gene induction.

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-beta (C/EBPbeta), 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/EBPbeta 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/EBPbeta and/or Nrf2. Immunoblot analysis revealed that M1 [4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one] and M2 (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine), but not M3 (7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine) and M4 (7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine), induced GSTA2 in H4IIE cells. M1 and M2 also increased the luciferase activity from pGL-1651, which contained the luciferase structural gene downstream of the -1.65-kilobase GSTA2 promoter region. Nuclear C/EBPbeta levels were enhanced by the metabolites but not by M3 or M4. Among the oxidized metabolites examined, only M2, which elicited cell death at a relatively high concentration, activated Nrf2, as indicated by nuclear accumulation of Nrf2 and its ARE binding activity. The present study provides evidence that M1 and M2, but not M3 and M4, induce GSTA2 and that M1 induces GSTA2 only via C/EBPbeta activation, whereas M2 does so by activating Nrf2 as well as C/EBPbeta. These results substantiate the differential effects of oltipraz's metabolites on C/EBPbeta- and/or Nrf2-mediated GSTA2 induction.