Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

Isoniazid (INH) is highly effective for the management of tuberculosis. However, it can cause liver injury and even liver failure. INH metabolism has been thought to be associated with INH-induced liver injury. This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.

Pyrazinamide (PZA) is an important component of a standard combination therapy against tuberculosis. However, PZA is hepatotoxic, and the underlying mechanisms are poorly understood. Biotransformation of PZA in the liver was primarily suggested behind its hepatoxicity. This review summarizes the knowledge of the key enzymes involved in PZA metabolism and discusses their contributions to PZA hepatotoxicity. SIGNIFICANCE STATEMENT This review outlines the current understanding of PZA metabolism and hepatotoxicity. This work also highlights the gaps in this field, which can be used to guide the future studies on PZA-induced liver injury.

Isoniazid (INH) is a synthetic anti-mycobacterial agent used to treat active or latent tuberculosis (TB). INH has been in clinical use for nearly 70 years and remains broadly utilized at the front line of anti-TB treatment. However, the potential for liver damage and even fulminant liver failure during INH-based TB treatment presents a major challenge for TB control programs worldwide. In this review, we discuss the hepatotoxic effects of INH and provide an overview of the mechanisms and their applications in prediction and prevention of INH hepatotoxicity in clinical practice.

Ritonavir (RTV) is on the World Health Organization’s list of essential medicines for antiretroviral therapy, but can cause hepatotoxicity by unknown mechanisms. Multiple clinical studies found that hepatotoxicity occurred in 100% of participants who were pretreated with rifampicin or efavirenz followed by RTV-containing regimens. Both rifampicin and efavirenz are activators of the pregnane X receptor (PXR), a transcription factor with marked interspecies differences in ligand-dependent activation. Using PXR-humanized mouse models, we recapitulated the RTV hepatotoxicity observed in the clinic. PXR was found to modulate RTV hepatotoxicity through CYP3A4-dependent pathways involved in RTV bioactivation, oxidative stress, and endoplasmic reticulum stress. In summary, the current work demonstrated the essential roles of human PXR and CYP3A4 in RTV hepatotoxicity, which can be applied to guide the safe use of RTV-containing regimens in the clinic.

The transporter ABCG2 determines phototoxicity and hepatotoxicity in erythropoietic protoporphyria.