SMBI organize a conference on Monday 10th november 2008
in the Faculty of Medicine and Pharmacy of Rabat, amphitheater "amphi ARAFA", Rabat
at 11h AM

Toxicogenomics and Toxicoproteomics: How to Improve Prediction and Mechanistic Understanding of Human Liver Toxicity

the conference will be presented by Pr. Mohammed Bourdi

Abstract: It has been found that adverse drug reactions (ADRs) are one of the top ten leading causes of death and illness in the developed world with direct medical costs billions of dollars annually in the Unite States. Although many factors influence the effect of medications (i.e. age, gender, organ function, drug interactions), genetic factors account for 20–95% of drug response variability and play a significant role in the incidence and severity of ADRs. Drug-induced liver disease (DILD), one of the important ADRs, represents a significant source of morbidity and mortality and a substantial challenge for drug therapy and new drug development. Despite the low incidence of DILD, it is one of the most frequent reasons cited for the withdrawal of drugs from the market, and it accounts for more than 50% of acute liver failure cases in the United States. Unfortunately, it remains difficult to accurately predict which new drugs will cause DILD and who will be at risk of developing this disease. This is due in large part to the lack of animal models for most drugs and resultant scarcity of information concerning both mechanisms of liver injury and the nature of risk factors that contribute to DILD susceptibility. However, from studies done with drugs that will cause liver injury in animals, it is clear that DILD can be initiated by reactive metabolites of drugs formed in hepatocytes. These metabolites may cause hepatocellular injury directly by covalently altering essential liver proteins or indirectly by promoting the formation of reactive oxygen and nitrogen species, which may also covalently modify liver proteins and lead in some cases to severe allergic hepatitis.

Mounting evidence suggests that DILD is a complex, multifactorial disease in which no one factor is likely to be an absolute indicator of susceptibility. As an approach to better understand the multifactorial basis of DILD, we compared the hepatic proteome of mice that are resistant (SJL) and susceptible (C57BL/6) to acetaminophen-induced liver disease (AILD), using solution-based isotope-coded affinity tag (ICAT) liquid chromatography mass spectrometry. Several novel factors were identified that were more highly expressed in the livers of SJL mice, including those involved in stress response, cell proliferation and tissue regeneration, and protein modification, implicating these proteins as potential hepatoprotective factors. There was also a selective loss of several mitochondrial proteins from the livers of the susceptible C57BL/6 mice, suggesting that the loss of functional mitochondria may indeed play a role in AILD. These findings indicate that comparative hepatic proteomic analyses of susceptible and resistant mouse strains may provide a global approach for identifying potential risk factors and mechanistic pathways responsible for DILD. We have also uncovered additional potential risk factors by comparing hepatic mRNA expression profiles of the same two strains of mice. Additionally, the results from both the proteomic and the genomic studies were compared. The two approaches were found to be complementary to each other and not simply overlapping. In conclusion, it appears that susceptibility to DILD may depend on the balance between many factors with the numerous protectors contributing to the relatively low incidence of DILD.  Perhaps polymorphisms in genes encoding for regulatory factors, may lead to the increase susceptibility of humans to DILD.