Factors Influencing Imatinib-Induced Hepatotoxicity

한지민,이정,조윤숙,곽혜선 대한암학회 2020 Cancer Research and Treatment Vol.52 No.1

Purpose Although imatinib-induced hepatotoxicity may aggravate the patient’s clinical condition and alter the treatment plan, the underlying mechanism of and factors influencing imatinibinduced hepatotoxicity have rarely been investigated. The purpose of this study was to investigate factors affecting on the incidence of hepatotoxicity within 90 days after starting imatinib treatment and time to onset of imatinib-induced hepatotoxicity. Materials and Methods We retrospectively evaluated the records of 177 patients receiving imatinib from October 2012 to September 2017. The analyzed factors included sex, age, body weight, body surface area, underlying disease, and concomitant drugs. Results The proportion of patients with hepatotoxicity within 90 days after imatinib administration was 33.9%. Proton pump inhibitors (PPIs) increased the incidence of hepatotoxicity approximately 3.8-fold and doubled the hazard of time to reach hepatotoxicity. Patients with liver disease or hepatitis B virus (HBV) carriers had a more than 8-fold higher risk of hepatotoxicity and a 5.2-fold increased hazard of hepatotoxicity compared to those without liver disease or HBV. Patients with body weight under 55 kg had a 2.2-fold higher risk for occurrence of hepatotoxicity. Patients with an imatinib dose > 400 mg had a 2.3-fold increased hazard of time to reach hepatotoxicity compared to those with an imatinib dose ! 400 mg. Conclusion The findings of this study suggest that the use of PPIs and presence of liver disease or HBV were associated with imatinib-induced hepatotoxicity. Thus, close liver function monitoring is recommended, especially in patients with liver impairment or using PPIs.

Hepatotoxicity and Related Risk Factors of Severe Hepatotoxicity among HIV-1 Infected Individuals Initiated on Highly Active Antiretroviral Therapy (HAART) in Cameroon

( Lem Edith Abongwa ),( Anthony Kebira Nyamache ),( Fokunang Charles ),( Judith Torimiro ),( Nshom Emmanuel ),( Irenee Domkam ),( Paul Okemo ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Hepatotoxicity due to highly active antiretroviral therapy (HAART) has gained prominent attention since it can be affected by many factors. The aim of this study was to determine the prevalence of hepatotoxicity and related risk factors of severe hepatotoxicity following HAART initiation. Methods: One hundred naive HIV-1 patients were recruited and followed up for 24 weeks. They were placed on either Tenofovir (TDF)+Lamivudine (3TC)+Efavirenz (EFV) or Zidovudine (AZT)+Lamivudine+Nevirapine (NVP) or Zidovudine+Lamivudine+Efavirenz regimen. Venous blood samples were collected to measure transaminotransferases (ALT and AST) and alkaline phosphatase (ALP), using colometric enzymatic reaction which were used to classified hepatotoxicity based on age and sex. Results: A total of 38(38%) and 55(55%) patients presented with hepatotoxicity while 15% and 28% of patients of them had severe hepatotoxicity at 4 and 24 weeks respectively. Serum levels of all enzymes increased significantly (P<0.05) with increased treatment duration. Univariate analysis revealed that the risk factor of developing severe hepatotoxicity was significantly (P<0.05) greater in patients <30years, males, low BMI, low monthly income earners and patient on AZT+3TC+ NVP regimen. While multivariate analysis showed that age <30 years, Low BMI, low monthly income and the use of AZT+3TC+NVP was an independent risk factors. Conclusions: Low BMI, <30years, low monthly income and the use of AZT+3TC+NVP regimen were identifiable risk factors for the development of severe hepatotoxicity. As such these factors should be considered as an important strategy by clinicians in preventing the hepatotoxicity.

Alcohol, NAFLD, Other : The Incidence and Risk Factors for Hepatotoxicity in Patients Undergoing Adjuvant Folfox Chemotherapy after Curative Resection for Colorectal Cancer

( Se Ok Lee ),( Dong Hyun Sinn ),( Geum Youn Gwak ),( Yong Han Paik ),( Moon Seok Choi ),( Joon Hyeok Lee ),( Kwang Cheol Koh ),( Seung Woon Paik ),( Byung Chul Yoo ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: FOLFOX chemotherapy (folinic acid + fluorouracil + oxaliplatin) is a standard adjuvant regimen following curative resection of colorectal cancer (CRC). Some patients undergoing FOLFOX chemotherapy are reported to experience chemotherapy-related hepatotoxicity; however, the incidence and risk factors for the development of hepatotoxicity in these patients are not well described. Patients and methods: A total of 849 patients aged between 17 and 79 years who were treated with adjuvant FOLFOX chemotherapy after curative resection for CRC were recruited from Samsung Medical Center in October 2005 to June 2012. Their medical records were retrospectively collected and analyzed. Hepatotoxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Results: Six hundreds and eighty six of 849 patients (80.8%) experienced hepatotoxicity during or shortly after FOLFOX chemotherapy, in which 586 were in grade 1, 84 in grade 2 and 16 patients in grade 3. However, most of these episodes were transient and spontaneously recovered. Risk factors associated with the development of any grade of hepatotoxicity were age < 60 years (HR 2.390, CI 1.667-3.425), female (HR 1.51, CI 1.038-2.234), baseline ALT>20 IU/mL (HR 1.717, CI 1.065- 2.768). Risk factors associated with the development of ≥ grade 2 of hepatotoxicity were age<60 years (HR 5.393, CI 2.951- 9.858), HCV carrier (HR 5.373, CI 1.181-24.442). There was no relation between the development of hepatotoxicity and obesity, baseline level of AST, PT (INR), cholesterol and platelet, and HBsAg status. Three of 22 HBsAg positive patients who were not given prophylactic antiviral treatment during FOLFOX chemotherapy did experience ≥ grade 2 of hepatotoxicity during or shortly after chemotherapy. However, the incidence was not different from those of HBsAg positive patients who were given antiviral therapy or HBsAg negative patients. All these three patients recovered without any specific treatment for HBV. Conclusion: Hepatotoxicity induced by adjuvant FOLFOX chemotherapy after curative resection for CRC is not uncommon; however, most episodes were mild and self-limited. Age<60 years and HCV carrier were risk factors for ≥ grade 2 of hepatotoxicity. Moreover, it is unlikely that a short course of FOLFOX chemotherapy influences HBV reactivation.

상승적 화학적 간독성에 미치는 YH439의 영향

김상건(Sang Geon Kim),조주연(Joo Youn Cho) 대한약리학회 1996 대한약리학잡지 Vol.32 No.3

간독성물질인 CCl₄의 대사에서 반응성이 높은 대사중간체의 증가가 P450 2E1의 활성 및 발현증가와 관련된다. YH439는 랫트에서 사염화탄소에 의하여 유발된 간 손상에 보호효과가 탁월하였고, 각종 독성물질에 의하여 발생하는 간염을 억제하며 P450 2E1의 발현을 억제하는 것으로 나타났다. P450 2E1의 발현억제가 YH439의 간장보호작용의 일부기전으로 해석되나 free radical 공격의 제어, 방어과정에 관련된 탐식세포의 역할등 간장독성에 관련된 YH439의 영향 및 관련된 기초연구는 완전히 확립되어 있지 않다. 본 연구에서는 상승적인 화학적 독성에 대한 YH439의 보호효과를 관찰하였다. Retinoyl palmiate (Vit-A)를 전처러하고 YH439를 처리한 rat의 경우 CCl₄ 단독투여군에 비하여 혈장 alanine aminotransferase (ALT)활성이 5배로 증가하여 CCl₄에 의한 간독성을 현저히 강화시켰으나, YH439와 Vit-A를 동시에 전처리한 rats에 있어서는 Vit-A에 의하여 강화된 독성이 94% 감소하였다. Vit-A에 의한 혈장 ALT 활성 증가는 Kupffer cell 활성을 선택적으로 억제하는 GdCl₃의 투여에 의해 완전히 차단되어 YH439가 Kupffer cell 활성억제를 매개로 상승적 간손상에 대하여 보호효과가 있음을 지지한다. Propyl sulfide의 전처치는 CCl₄에 의해 유도되는 간독성을 CCl₄ 단독투여와 비교했을때 5배 이상 증가시켰으나, Propyl sulfide와 YH439를 병용투여할 경우 propyl sulfide에 의해 강화되는 간독성이 YH439의 투여용량에 의존적으로 감소하였고, propyl sufide와 CCl₄에 의한 지질과산화의 증가가 YH439에 의하여 용량의존적으로 억제되는 것으로 나타났다. Propyl sulfide에 의하여 강화된 간독성의 차단은 YH439가 P450 2E1 발현조절을 통하여 간독성을 제어함을 지지한다. 그러나 YH439는 pyridine과 CCl₄에 의한 독성을 억제시키지 못하였다. 이는 Pyridine에 의해 유도되는 다른 형의 P450발현이 YH439에 의해 억제되지 못하는 이유로 해석된다. 중금속에 의해 유도되는 간독성에 대한 YH439의 보호효과를 ICR mice에서 관찰하였을 때 CdCl₂를 1회 투여할때 ALT와 aspartate aminotransferase (AST)활성이 5 ~ 6배 증가하였으나 YH439를 투여한 후 CdC1₂를 투여한 동물에 있어서는 투여후 6시간에 AST의 증가가 유의성 있게 억제되었다. 그러나 YH439는 thioacetamide에 의하여 유발된 liver fibrosis에는 개선효과가 없는 것으로 나타났다. 이러한 결과는 YH439가 Kupffer cell 불활성화를 통하여 Vit-A에 의해 유도되는 간독성을 효과적으로 방어하고, YH439에 의한 P450 2E1의 발현억제는 propyl sulfide를 경유하는 간독성 차단과 관계되며, YH439는 중금속으로 유도된 조직독성에 방어효과가 있음을 지지한다. The reactive intermediates formed during the metabolism of therapeutic agents, toxicants and carcinogens by cytochromes P450 are frequently capable of covalently binding to tissue macromolecules and causing tissue damage. It has been shown that YH439, a congener of malotilate, is effective in suppressing hepatic P450 2E1 expression. The present study was designed to further establish the mechanistic basis of YH439 protection against toxicant by assessing its effects against chemical-mediated potentiated hepatotoxicity. Retinoyl palmitate (Vit-A) pretreatment of rats for 7 days substantially enhanced carbon tetrachloride hepatotoxicity, as supported by an ~ 5-fold increase in serum alanine aminotransferase (ALT) activity, as compared to CCl₄ treatment alone. The elevation of ALT activity due to Vit-A was completely blocked by the treatment of GdCl₃ a selective inhibitor of Kupffer cell activity. Concomitant pretreatment of rats with both YH439 and Vit-A resulted in a 94% decrease in Vit-A-potentiated CCl₄ hepatotoxicity. YH439 was also effective against propyl sulfide-potentiated CCl₄-induced hepatotoxicity. Whereas propyl sulfide (50 mg/kg, 7d) enhanced CCl₄-induced hepatotoxicity by >5-fold, relative to CCl₄ treatment alone, concomitant treatment of animals with both propyl sulfide and YH439 at the doses of 100 and 200 mg/kg prevented propyl sulfide-potentiated CCl₄ hepatotoxicity by 35% and 90%, respectively. Allyl sulfide, a suppressant of hepatic P450 2E1 expression, completely blocked the propyl sulfide-enhanced hepatotoxicity, indicating that propyl sulfide potentiation of CCl₄ hepatotoxicity was highly associated with the expression of P450 2E1 and that YH439 blocked the propyl sulfide-enhanced hepatotoxicity through modulation of P450 2E1 levels. Propyl sulfide- and CCl₄-induced stimulation of lipid peroxidation was also suppressed by YH439 in a dose-related manner, as supported by decreases in malonedialdehyde production. The role of P450 2E1 induction in the potentiation of CCl₄ toxicity and the effects of YH439 were further evaluated using pyridine as a P450 2E1 inducer. Pyridine pretreatment substantially enhanced the CCl₄ hepatotoicity by 23-fold, relative to CCl₄ alone. YH439, however, failed to reduce the pyridine-potentiated toxicity, suggesting that the other form(s) of cytochroms P450 inducible by pyridine, but not suppressible by YH439 treatment, may play a role in potentiating CCl₄-induced hepatotoxicity. YH439 was capable of blocking cadmium chloride-induced liver toxicity in mice. These results demonstrated that YH439 efficiently blocks Vit-A-enhanced hepatotoxiciy through Kupffer cell inactivation and that the suppression of P450 2E1 expression by YH439 is highly associated with blocking of propyl sulfide-mediated hepatotoxicity.

The Effects of Isopropyl 2-(1,3-dithioetane-2-ylidene)-2-[N-(4-methyl-thiazol-2-yl)carbamoyl]acetate (YH439) on Potentiated Carbon Tetrachloride Hepatotoxicity

김상건,조주연,Kim, Sang-Geon,Cho, Joo-Youn The Korean Society of Pharmacology 1996 대한약리학잡지 Vol.32 No.3

간독성물질인 $CCl_4$의 대사에서 반응성이 높은 대사중간체의 증가가 P450 2E1의 활성 및 발현증가와 관련된다. YH439는 랫트에서 사염화탄소에 의하여 유발된 간 손상에 보호효과가 탁월하였고, 각종 독성물질에 의하여 발생하는 간염을 억제하며 P450 2E1의 발현을 억제하는 것으로 나타났다. P450 2E1의 발현억제가 YH439의 간장보호작용의 일부기전으로 해석되나 free radical 공격의 제어, 방어과정에 관련된 탐식세포의 역할등 간장독성에 관련된 YH439의 영향 및 관련된 기초연구는 완전히 확립되어 있지 않다. 본 연구에서는 상승적인 화학적 독성에 대한 YH439의 보호효과를 관찰하였다. Retinoyl palmiate (Vit-A)를 전처러하고 YH439를 처리한 rat의 경우 $CCl_4$ 단독투여군에 비하여 혈장 alanine aminotransferase (ALT)활성이 5배로 증가하여 $CCl_4$에 의한 간독성을 현저히 강화시켰으나, YH439와 Vit-A를 동시에 전처리한 rats에 있어서는 Vit-A에 의하여 강화된 독성이 94% 감소하였다. Vit-A에 의한 혈장 ALT 활성 증가는 Kupffer cell 활성을 선택적으로 억제하는 $GdCl_3$의 투여에 의해 완전히 차단되어 YH439가 Kupffer cell 활성억제를 매개로 상승적 간손상에 대하여 보호효과가 있음을 지지한다. Propyl sulfide의 전처치는 $CCl_4$에 의해 유도되는 간독성을 $CCl_4$ 단독투여와 비교했을때 5배 이상 증가시켰으나, Propyl sulfide와 YH439를 병용투여할 경우 propyl sulfide에 의해 강화되는 간독성이 YH439의 투여용량에 의존적으로 감소하였고, propyl sufide와 $CCl_4$에 의한 지질과산화의 증가가 YH439에 의하여 용량의존적으로 억제되는 것으로 나타났다. Propyl sulfide에 의하여 강화된 간독성의 차단은 YH439가 P450 2E1 발현조절을 통하여 간독성을 제어함을 지지한다. 그러나 YH439는 pyridine과 $CCl_4$에 의한 독성을 억제시키지 못하였다. 이는 Pyridine에 의해 유도되는 다른 형의 P450발현이 YH439에 의해 억제되지 못하는 이유로 해석된다. 중금속에 의해 유도되는 간독성에 대한 YH439의 보호효과를 ICR mice에서 관찰하였을 때 $CdCl_2$를 1회 투여할때 ALT와 aspartate aminotransferase (AST)활성이 $5{\sim}6$배 증가하였으나 YH439를 투여한 후 $CdC1_2$를 투여한 동물에 있어서는 투여후 6시간에 AST의 증가가 유의성 있게 억제되었다. 그러나 YH439는 thioacetamide에 의하여 유발된 liver fibrosis에는 개선효과가 없는 것으로 나타났다. 이러한 결과는 YH439가 Kupffer cell 불활성화를 통하여 Vit-A에 의해 유도되는 간독성을 효과적으로 방어하고, YH439에 의한 P450 2E1의 발현억제는 propyl sulfide를 경유하는 간독성 차단과 관계되며, YH439는 중금속으로 유도된 조직독성에 방어효과가 있음을 지지한다. The reactive intermediates formed during the metabolism of therapeutic agents, toxicants and carcinogens by cytochromes P450 are frequently capable of covalently binding to tissue macromolecules and causing tissue damage. It has been shown that YH439, a congener of malotilate, is effective in suppressing hepatic P450 2E1 expression. The present study was designed to further establish the mechanistic basis of YH439 protection against toxicant by assessing its effects against chemical-mediated potentiated hepatotoxicity. Retinoyl palmitate (Vit-A) pretreatment of rats for 7 days substantially enhanced carbon tetrachloride hepatotoxicity, as supported by an ${\sim}5-fold$ increase in serum alanine aminotransferase (ALT) activity, as compared to $CCl_4$ treatment alone. The elevation of ALT activity due to Vit-A was completely blocked by the treatment of $GdCl_3$ a selective inhibitor of Kupffer cell activity. Concomitant pretreatment of rats with both YH439 and Vit-A resulted in a 94% decrease in Vit-A-potentiated $CCl_4$ hepatotoxicity. YH439 was also effective against propyl sulfide-potentiated $CCl_4-induced$ hepatotoxicity. Whereas propyl sulfide (50 mg/kg, 7d) enhanced $CCl_4-induced$ hepatotoxicity by >5-fold, relative to $CCl_4$ treatment alone, concomitant treatment of animals with both propyl sulfide and YH439 at the doses of 100 and 200 mg/kg prevented propyl sulfide-potentiated $CCl_4$ hepatotoxicity by 35% and 90%, respectively. Allyl sulfide, a suppressant of hepatic P450 2E1 expression, completely blocked the propyl sulfide-enhanced hepatotoxicity, indicating that propyl sulfide potentiation of $CCl_4$ hepatotoxicity was highly associated with the expression of P450 2E1 and that YH439 blocked the propyl sulfide-enhanced hepatotoxicity through modulation of P450 2E1 levels. Propyl sulfide- and $CCl_4-induced$ stimulation of lipid peroxidation was also suppressed by YH439 in a dose-related manner, as supported by decreases in malonedialdehyde production. The role of P450 2E1 induction in the potentiation of $CCl_4$ toxicity and the effects of YH439 were further evaluated using pyridine as a P450 2E1 inducer. Pyridine pretreatment substantially enhanced the $CCl_4$ hepatotoicity by 23-fold, relative to $CCl_4$ alone. YH439, however, failed to reduce the pyridine-potentiated toxicity, suggesting that the other form(s) of cytochroms P450 inducible by pyridine, but not suppressible by YH439 treatment, may play a role in potentiating $CCl_4-induced$ hepatotoxicity. YH439 was capable of blocking cadmium chloride-induced liver toxicity in mice. These results demonstrated that YH439 efficiently blocks Vit-A-enhanced hepatotoxiciy through Kupffer cell inactivation and that the suppression of P450 2E1 expression by YH439 is highly associated with blocking of propyl sulfide-mediated hepatotoxicity.

소아 급성림프구성백혈병 환자에서 Sulfamethoxazole/ Trimethoprim에 의한 간독성 및 관련인자

이주연,박유빈,홍석민,장혜진,김성환,조은정,조윤숙,강형진 대한약물역학위해관리학회 2024 약물역학위해관리학회지 Vol.16 No.1

: This study aimed to examine the causality of hepatotoxicity related to sulfamethoxazole/trimethoprim (SMX/TMP) in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: We retrospectively analyzed medical records of pediatric ALL patients, who were transitioned from SMX/TMP to aerosolized pentamidine (AP) for Pneumocystis jirovecii pneumonia prevention due to suspected hepatotoxicity between 2010 and 2023. The Roussel Uclaf causality assessment method (RUCAM) was used to assess hepatotoxicity due to SMX/ TMP, emphasizing cases considered “high probability” (RUCAM ≥ 6). Results: Of the 176 pediatric ALL patients who switched from SMX/TMP to AP, 112 did so due to elevated liver enzyme levels, and 38 of these (33.9%) were classified as “high probability” for hepatotoxicity according to RUCAM. Hepatotoxicity induced by SMX/TMP is characterised by an average ALT level of 430.6 IU/L, a total bilirubin level of 1.2 mg/dL at onset, typically manifesting after 223.1 days and resolving within 110.7 days. Multivariable analysis identified significant factors such as age (1–5 years), obesity, onset time (≤ 20 days), recovery time (≤ 20 days), and treatments with L-asparaginase and 6-mercaptopurine as associated with an increased risk of hepatotoxicity. Conclusion: This study found that 21.6% of pediatric ALL patients who discontinued SMX/TMP for prophylaxis had hepatotoxicity with a ‘probable or higher’ causality due to SMX/TMP. Identifying factors associated with ‘probable or higher’ causality for SMX/TMP-induced hepatotoxicity in these patients may be valuable for future research in this domain. (PeRM 2024;16:49-56)

티로신 키나아제 저해제의 간독성에 대한 고찰

한지민,곽혜선 한국임상약학회 2019 한국임상약학회지 Vol.29 No.4

Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.

베이지안 모델 기반 약물유사 화합물의 간 독성 예측

채한화(Han-Ha Chai),박원철(Wonchoul Park),진영배(Yeoung Bae Jin),임다정(Dajeong Lim) 한국산학기술학회 2024 한국산학기술학회논문지 Vol.25 No.1

Predicting hepatotoxicity is an important component of safety-related evaluations of drug-like compounds. Hepatotoxicity is related to the physicochemical properties of drug-like compounds, especially their structural alerts. In this study, we developed a Bayesian model to predict the hepatotoxicities of 498 drug-like compounds based on their quantitative structure-toxicity relationships (QSAR). The devised model predicted the hepatotoxicity of these compounds using 25 structural descriptors (such as the ECFP6 fingerprint) and provided a sensitivity, specificity, and concordance of 97.2%, 86.9%, and 90.6%, respectively. The model also successfully classified the 498 drug-like compounds by hepatotoxicity. In addition, TOPKAT<SUP>@</SUP> toxicity models were used to predict hepatotoxic effects related to toxicological endpoints (i.e., LD50, LOAEL) and liver injury-related potentials, such as Ames mutagenicity, carcinogenicity in male and female mice, and developmental toxicity potentials. Our results indicate that combined use of the devised Bayesian hepatotoxicity prediction model and the TOPKAT<SUP>@</SUP> hepatotoxicity model could replace experimental safety assessments of drug-like compounds. Accordingly, adopting the devised Bayesian toxicity model would reduce the time and cost of animal-based toxicity research by considering the safety and effectiveness of candidate compounds.

Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

정인아,박종선,조영재,윤호일,송정한,이춘택,이재호 대한의학회 2015 Journal of Korean medical science Vol.30 No.2

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-inducedhepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whetheranti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH),rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in bloodsamples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liverfunction test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between thehepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included inthe study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanineaminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showedPZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However,intergroup differences in the serum levels of the 4 anti-TB drugs were not statisticallysignificant. Basal serum drug concentration was not associated with the risk anti-TB DIH inpatients being treated with the currently recommended doses of first-line anti-TBtreatment drugs.

Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity

( Minjeong Kim ),( Jun-won Yun ),( Kyeho Shin ),( Yejin Cho ),( Mijeong Yang ),( Ki Taek Nam ),( Kyung-min Lim ) 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.2

Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix GeneChip^® Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.