17 - Toxicogenetic markers of liver dysfunction

Summary

Introduction

Toxicogenetics is the study of the genetic basis for variability in toxic injury – in this instance, toxic liver injury. It differs in three ways from pharmacogenetics – the genetic basis for variability in drug disposition – through its consideration of: (i) toxic (liver) injury rather than drug disposition; (ii) genetic variability in pathways that both induce and prevent toxic liver injury; and (iii) causes of damage wider than iatrogenic (drug-induced) injury. These additional causes of toxic liver injury may include other xenobiotics (e.g. environmental toxins), liver trauma and pathology (e.g. ischaemia/reperfusion injury), pathogens (e.g. hepatitis viruses) and extremes of physiological function (e.g. oxidative stress secondary to iron accumulation in haemochromatosis). Characteristic sequelae of all these primary mediators of toxic liver injury are a progression to oxidative stress and the production of secondary mediators of liver damage. The former reflects a shift of the cell's redox status away from its customary reduced status and the latter includes production of tumour necrosis factor (TNF) and cytokines by nonparenchymal cells.

The quantitative study of the consequences of toxicogenetic gene expression – toxicogenomics – is considered by Tugwood and Beckett in Chapter 28.

How can genetic diversity affect toxic liver injury?

Toxicogenetic diversity may determine the extent of expression of both the original toxic insult and the secondary response it elicits, as well as the function of endogenous cytoprotection.