Liver Injury by Drugs Metabolized via Cytochrome P450
DOI:
https://doi.org/10.12970/2308-8044.2020.08.12Keywords:
Cytochrome P450, CYP isoforms, DILI, Drug induced liver injury, Roussel Uclaf Causality Assessment Method, RUCAM.Abstract
Idiosyncratic drug induced liver injury (iDILI) is a rare pathological condition in predisposed individuals, whereby the immune system likely plays a major contributory role for initiation and perpetuation of the liver injury. The initiation of an immune response requires the activation of the innate immune system to the adaptive immune system through antigen presenting cells by molecules such as danger-associated molecular pattern molecules (DAMPs). Poorly understood is the role of cytochrome P450 (CYP) in triggering and perpetuating iDILI. For example, among 36 drugs implicated in iDILI assessed for causality by RUCAM, 22/36 drugs (61.1%) are metabolized via CYP, suggesting that reactive oxygen species (ROS) generated during the catalytic CYP cycle are involved in triggering the liver injury by these drugs. In this context, ROS could modify hepatic RNA, which after activation could code for proteins functioning as antigens and activating the innate immune system to the adaptive immune system. Characterized by immunological features including CYP antibody generation, liver injury by halothane is a perfect example for iDILI caused by a drug metabolized by CYP. Further clinical studies are needed to verify or dismiss this proposal.References
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