Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis

Abstract

Tyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM) for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis), all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism), imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib), and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism.

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…Moreover, cellular depletion of GSH increased cytotoxicity . These results concur with those of Paech et al using rifampicin in HepaRG cells and those of Teo et al, who reported an increased hepatotoxicity upon dexamethasone treatment both in vitro and in vivo. Eno et al studied the comparative effects of lapatinib 30 and O ‐dealkylated lapatinib 31 on HepG2 cells.…”

“…However, as far as TKI are concerned, very few data support the role of RM rather than the parent drug in TKI‐induced hepatotoxicity; these cases are discussed in this section. However, reporting the current state of knowledge of the entire spectrum of toxicity mechanisms at a cellular level is beyond the scope of this review …”

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

“…14–16,54,55 Paech et al recently reported an investigation on the mechanisms of hepatocellular toxicity of sunitinib and other tyrosine kinase inhibitors (imatinib, erlotinib, and lapatinib) in HepG2 and HepaRG cells. 56 Treatment of HepG2 cells with sunitinib was shown to increase the production of reactive oxygen species, disrupt the mitochondrial membrane potential, deplete glutathione content, and induce apoptosis in a concentration-dependent manner. 56 In the metabolically competent cell line Hep-aRG, 57,58 the cytotoxic effects of sunitinib increased following induction by rifampin, compared with sunitinib treatment alone.…”

“…56 Treatment of HepG2 cells with sunitinib was shown to increase the production of reactive oxygen species, disrupt the mitochondrial membrane potential, deplete glutathione content, and induce apoptosis in a concentration-dependent manner. 56 In the metabolically competent cell line Hep-aRG, 57,58 the cytotoxic effects of sunitinib increased following induction by rifampin, compared with sunitinib treatment alone. 56 This finding suggests that formation of toxic metabolite(s) may be involved in sunitinib-induced hepatotoxicity, but the parent drug itself may also be involved in mediating some of the hepatotoxic effects associated with sunitinib.…”

Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

“…Paech et al, examined the toxic effects of four tyrosine kinase inhibitors (imatinib, sunitinib, lapatinib, and erlotinib) in HepG2 cells, HepaRG cells, and isolated mouse liver mitochondria [65]. In HepG2 cells, cytotoxicity, as characterized by the release of adenylate kinase, was shown for sunitinib at 5–10 µM, and for lapatinib at 10–20 µM, after 24–48 h of incubation.…”