Associate Dean, Research and Graduate Studies, College of Pharmacy
Director, Southwest Environmental Health Science Center
Professor, Public Health
Numerous drug-induced and environmental exposure-related toxicities are the result of inter-individual variation in the ADME processes of absorption, distribution, metabolism and elimination that control the fate of these compounds from the body. Alterations in these processes provide the mechanistic basis for individual variability in response to drugs and environmental exposures. A common perception is that variability in response is due to genetic polymorphisms within the drug metabolizing enzyme and transporter genes. While there are numerous examples of these differences that play a major role in the susceptibility of genetic subpopulations for specific toxicities, the potential for transient phenotypic conversion due to temporary environmental changes, such as inflammation and disease, are often overlooked.
Due to the ensuing liver damage caused by the progressive stages of Non-Alcoholic Fatty Liver Disease (NAFLD), gene expression patterns can change dramatically resulting in a phenoconversion resembling genetic polymorphisms. Because the liver plays such a key role in the metabolism and disposition of xenobiotics, this temporary phenoconversion could lead to the inability of patients to properly metabolize and excrete drugs and environmental toxicants, increasing the risk of some adverse drug reactions and environmental toxicities.
Our group has made significant strides in identifying liver-specific disturbances in the expression and function of xenobiotic biotransformation enzymes and membrane drug transporters. Importantly, these molecular alterations in the expression and function of drug transporters and biotransformation enzymes lead to in vivo perturbations in the disposition of numerous xenobiotics.
Therefore, we suggest that patients with NAFLD present as a subpopulation of individuals that are at higher risk for developing ADRs, due to aberrant disposition of drugs and other xenobiotics. Specifically, our group has documented individual differences in ADME genes and proteins, such as metabolizing enzymes and transporters that cause a profound alteration in the pharmacokinetics, overall exposure, and toxicity of clinically relevant drugs and xenobiotics.