Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury

Abstract Background Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in hepatocytes. Hepatocytes can be accurately evaluated for drug-mediated CYP3A4 induction; this is the gold standard for in vitro hepatic toxicology testing. However, the variation from lot to lot is an issue that needs to be addressed. Only a limited number of immortalized hepatocyte cell lines have been reported. In this study, immortalized cells expressing CYP3A4 were generated from a patient with drug-induced liver injury (DILI). Methods To generate DILI-derived cells with high expression of CYP3A4, a three-step approach was employed: (1) Differentiation of DILI-induced pluripotent stem cells (DILI-iPSCs); (2) Immortalization of the differentiated cells; (3) Selection of the cells by puromycin. It was hypothesized that cells with high cytochrome P450 gene expression would be able to survive exposure to cytotoxic antibiotics because of their increased drug-metabolizing activity. Puromycin, a cytotoxic antibiotic, was used in this study because of its rapid cytocidal effect at low concentrations. Results The hepatocyte-like cells differentiated from DILI-iPSCs were purified by exposure to puromycin. The puromycin-selected cells (HepaSM or SI cells) constitutively expressed the CYP3A4 gene at extremely high levels and exhibited hepatocytic features over time. However, unlike primary hepatocytes, the established cells did not produce bile or accumulate glycogen. Conclusions iPSC-derived hepatocyte-like cells with intrinsic drug-metabolizing enzymes can be purified from non-hepatocytes and undifferentiated iPSCs using the cytocidal antibiotic puromycin. The puromycin-selected hepatocyte-like cells exhibited characteristics of hepatocytes after immortalization and may serve as another useful source for in vitro hepatotoxicity testing of low molecular weight drugs.

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Outcomes of TB/HIV co-infected patients presenting with antituberculosis drug-induced liver injury

South African Medical Journal ◽

10.7196/samj.8217 ◽

2015 ◽

Vol 105 (5) ◽

pp. 393 ◽

Cited By ~ 6

Author(s):

S Naidoo ◽

D Evans ◽

E Jong ◽

K Mellet ◽

R Berhanu

Keyword(s):

Liver Injury ◽

Antituberculosis Drug ◽

Drug Induced ◽

Drug Induced Liver Injury

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Genetic Risk Factors in Drug‐Induced Liver Injury Due to Isoniazid‐Containing Antituberculosis Drug Regimens

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.2100 ◽

2020 ◽

Author(s):

Paola Nicoletti ◽

Harshad Devarbhavi ◽

Ashish Goel ◽

Radha Venkatesan ◽

Chundamannil E. Eapen ◽

...

Keyword(s):

Risk Factors ◽

Liver Injury ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Antituberculosis Drug ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Drug Regimens

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Prophylactic Therapy of Silymarin (Milk Thistle) on Antituberculosis Drug-Induced Liver Injury: A Meta-Analysis of Randomized Controlled Trials

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2019/3192351 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Lina Tao ◽

Xiaoyu Qu ◽

Yue Zhang ◽

Yanqing Song ◽

Si-xi Zhang

Keyword(s):

Liver Injury ◽

Liver Function ◽

Randomized Controlled Trials ◽

Controlled Trials ◽

Cochrane Central Register ◽

Prophylactic Therapy ◽

Antituberculosis Drug ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Randomized Controlled

Background. Prophylactic therapy with silymarin to prevent the development of antituberculosis drug-induced liver injury (anti-TB DILI) has been under debate. We aimed to evaluate the effect of silymarin in the prevention of anti-TB DILI. Methods. We searched MEDLINE, PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to 30th November 2018. Randomized controlled trials (RCTs) that compared silymarin and placebo to prevent anti-TB DILI were included. All statistical analyses were conducted using STATA 12.0 software. Standardized mean difference (SMD) and risk ratio (RR) with 95% confidence intervals (CIs) were used to evaluate the effect of silymarin. The quality of included studies was assessed according to Cochrane handbook. Funnel plots and Egger’s tests were carried out to evaluate publication bias. Sensitivity analysis was conducted to assess the influence of each study. Results. A total of 1198 patients from five RCTs (585 with silymarin and 613 with placebo groups) were included. Overall, silymarin significantly reduced the occurrence of anti-TB DILI at week 4 [RR: 0.33, 95% CI (0.15, 0.75)]. In addition, silymarin exerted protective effect on liver function in patients undergoing anti-TB drugs [SMD = − 0.15, 95% CI (−0.24, −0.07), P < 0.001 (ALT); SMD =−0.14, 95% CI (−0.23, −0.06), P = 0.001(AST); SMD =−0.12, 95% CI (−0.20, −0.03), P = 0.008 (ALP)]. Silymarin led to similar AEs in placebo groups [OR: 1.09, 95% CI (0.86, 1.39), P = 0.47]. Conclusion. Prophylactic therapy of silymarin is contributed to a noticeably reduced risk of development of anti-TB DILI four weeks after the initiation. In addition, silymarin significantly improved the liver function in patients who are receiving anti-TB drugs.

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