The molecular basis of cytochrome P450 and UDP-glucuronosyltransferase isoform substrate selectivity [ 2004 - 2006 ]

Research Grant

Researchers: Prof John Miners (Principal investigator) ,  Dr Paul Smith ,  E/Pr Peter Mackenzie

Brief description Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in humans primarily responsible for the metabolism of drugs and other chemicals; cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Indeed, CYP and UGT are together responsible for the elimination of over 90% of metabolised drugs in humans. Both UGT and CYP exist as superfamilies of structurally related enzymes (called 'isoforms'). Approximately fifteen CYP isoforms are known to metabolise drugs, and a similar number of UGT isoforms also appear to have the capacity to metabolise drugs in humans. The separate CYP and UGT isoforms preferentially metabolise different types of drugs and chemicals, due to the fact each isoform comprises a different sequence of amino acids. However, which of the approximately 500 amino acids present in each UGT and CYP isoform that bind and metabolise specific drugs and chemicals is unknown. This project will identify the individual amino acids of several important CYP and UGT isoforms responsible for binding and metabolising drugs and other chemicals. A variety of techniques will be used, including modification of the amino acid sequence of the isoforms and computer modelling of their 'internal' structure. Elucidating the structural basis of how drugs and chemicals interact with CYP and UGT isoforms is fundamental to our understanding of these important enzymes and their function, and can be used to design drugs with better metabolic stability and decreased propensity for troublesome interactions with other drugs.

Funding Amount $AUD 448,500.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant