Laboratory and genetic markers for assessing liver function to predict drug metabolism and detect drug-induced liver injury

Abstract

Introduction: To date, liver function is measured with general liver function tests and requires assessment prior treatment in vulnerable patient groups, as it influences drug metabolism. CYP450 enzymes in the liver play an important role in drug metabolism. An effective and safe treatment will only be achieved when plasma drug concentrations are within a therapeutic window. Therefore, assessing liver function prior treatment is needed to predict drug response. The available general liver function tests lack the ability to predict specific drug metabolism. Therefore, new biomarkers and genetic mutations for measuring the liver metabolic capacity to predict drug metabolism are needed for moving towards personalized medicine. In addition, biomarkers for early detection of drug-induced liver injury (DILI) to prevent further liver damage are of great importance.

Aim: The objective of this review is to investigate and identify laboratory and genetic markers that assess liver function to predict drug metabolism. Additionally, biomarkers for the early detection of DILI will be explored.

Method: A literature review was conducted in the Pubmed database, on May 3, 2024. Only English literature was reviewed, case studies and congress articles were excluded. No further exclusion criteria or date restriction were applied.

Results: First, biomarkers assessing liver injury in general include AST, ALT, bilirubin, HA, ADMA, RBP4, resistin, and XOR. However, these markers are not suitable for predicting an individual’s drug response. Laboratory markers found for drug metabolizing enzymes in the liver, include miRNAs (CYP2B6), 4βOHC (CYP3A), bile acids (CYP3A), TG/AG (UGT2B17), ratios 2-PY and 4-PY to NMN (AOX), and plasma levels of CES1. Second, multiple polymorphisms are found for both regulatory genes and drug metabolizing enzymes. Third, early detection of DILI may be achieved via miRNA-122, K18, GLDH, HMGB1, MCSFR1 and OPN.

Conclusion: In this review, an overview is provided concerning currently known laboratory and genetic markers for predicting drug response and detecting early DILI. Biomarkers with greatest potential for predicting drug response are miRNAs for CYP2B6 activity, the 4βOHC:cholesterol ratio and bile acids for CYP3A activity. These biomarkers still need validation in future studies, and more endogenous biomarkers measuring CYP450 enzyme activities need to be found. Additionally, genotyping has great potential in finding polymorphisms in CYP450 enzymes itself as well as regulatory genes, to predict drug metabolism. Lastly, early detection of DILI both miRNA-122 and K18 have greatest potential, due to liver-specificity and earlier detection compared to ALT. Still, the ideal biomarker has not been found.