SIMULTANEOUS MEASUREMENT OF HUNDREDS OF LIVER PROTEINS - APPLICATION IN ASSESSMENT OF LIVER-FUNCTION

Proteins implement most biological functions at the molecular level. A s one might expect based on this fact, it appears that the altered fun ctional states associated with toxic effects involve changes in the ab undance or structure of proteins. Although numerous specific assays ex ist to measure changes in the abundance of individual proteins, practi cal limitations have prevented widespread use of multiple protein assa ys for the global characterization of toxicity. Recent developments in protein analytical technology are rapidly changing this picture. Two- dimensional gel electrophoresis, a technique capable of resolving and quantitating hundreds of proteins simultaneously, is becoming an autom ated, high-throughput tool. In parallel, techniques have been develope d that allow the resulting deluge of protein measurements to be organi zed into a prototype Molecular Effects Database(TM) describing xenobio tic effects in rodent liver. This database can detect, classify, and c haracterize a broad range of liver toxicity mechanisms. It currently c ontains approximately 10 million protein measurements, including data on the liver effects of 43 compounds, with a further 50 compounds to b e added in 1995. Observed effects range from very broad (sex steroids alter levels of 45% of all liver proteins) to very specific (e.g., hep atic hydroxymethyl glutaryl coenzyme A reductase inhibitors). Companio n 2-dimensional databases describing rodent brain and kidney have been initiated, as have linkages to the genomic sequence databases. Assimi lation of this approach into research and regulatory toxicology poses an interesting challenge-one that is likely to lead to a radically mor e sophisticated understanding of toxicity and its biological basis.