Roles of the ABCG2 transporter in protoporphyrin IX distribution and toxicity.

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy. Significance Statement This review summarized the roles of ABCG2 in modulating PPIX distribution and highlighted the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated toxicity.

Roles of Cofactors in Drug-Induced Liver Injury: Drug Metabolism and Beyond.

Drug-induced liver injury (DILI) remains one of the major concerns for healthcare providers and patients. Unfortunately, it is difficult to predict and prevent DILI in the clinic because detailed mechanisms of DILI are largely unknown. Many risk factors have been identified for both "intrinsic" and "idiosyncratic" DILI, suggesting that cofactors are an important aspect in understanding DILI. This review outlines the cofactors that potentiate DILI and categorizes them into two types: (1) the specific cofactors that target metabolic enzymes, transporters, antioxidation defense, immune response, and liver regeneration; and (2) the general cofactors that include inflammation, age, gender, comorbidity, gut microbiota, and lifestyle. The underlying mechanisms by which cofactors potentiate DILI are also discussed. SIGNIFICANCE STATEMENT: This review summarizes the risk factors for DILI, which can be used to predict and prevent DILI in the clinic. This work also highlights the gaps in the DILI field and provides future perspectives on the roles of cofactors in DILI.