Table 2. Drugs that cause DIFLD and proposed mechanisms responsible for their toxicity.

Drugs that cause DIFLD	Proposed mechanisms
Amiodarone	Blockage of CPT1 enzyme activity, blockage of mtFAO, increase in acetylcarnitine levels, inhibition of MRC I and II complexes. Trigger of de novo lipogenesis by augmenting SREBP1, THRSP, ACLY, FASN, SCD1 PLIN4, ADFP genes’ expression. Reduction in GSH levels
Tamoxifen	Impairment of the mtFAO, induction of de novo lipogenesis by upregulation of SREBP1c and its downstream genes. Stimulation of MTP expression and VLDL assembly and secretion. Reduction in GSH levels
Methotrexate	Effect on mitochondrial activity by hampering of folate entry into mitochondria, generation of ROS, disruption of the intestinal epithelial barrier
5-Fluorouracil, irinotecan, l-asparaginase	Impairment of mtFAO and enhancement of ROS accumulation in hepatocytes
Valproate	Competition with other FFAs for mtFAO, decrease in CoA levels. Induction of systemic insulin resistance and weight gain
Tetracycline	Inhibition of MTP enzyme, decrease in the PAARα, CPTI and FABP1 genes’ expression, which are all involved in mtFAO. Enhancement of ROS generation by activation of ATF4
NRTIs	Inhibition of human DNA polymerase γ, decrease in mitochondrial DNA replication, induction of oxidative stress

ACLY, ATP-citrate synthase; ADFP, adipose differentiation-related protein; ATF4, transcription factor 4; CoA, coenzyme A; CPT1, carnitine palmitoyltransferase-1; CPTI, carnitine palmitoyltransferase I; FABP-1, fatty acid-binding protein 1; FASN, fatty acid synthase; FFA, free fatty acid; GSH, glutathione; MTP, microsomal triglyceride transfer protein; PLIN4, perilipin-4; SCD1, stearoyl-CoA desaturase; SREBP1, sterol regulatory element-binding protein 1; THRSP, thyroid hormone-inducible hepatic protein.