Molecular Modeling of the Metabolism of Acetaminophen and

Abstract

Paracetamol, or acetaminophen, is a common analgesic and fever-reducer. There are three major metabolic pathways for acetaminophen in the liver. The final products of each pathway are nontoxic and are excreted by the kidneys. Cresol and similar molecules are competitors with acetaminophen for metabolism in the gut. We can compare the metabolism of acetaminophen with alternate molecular structures—such as cresols—using a QSAR analysis of each molecule. We compute the dipole moments, hydrogen bonding capabilities, electron density and HOMO/LUMO energies of these molecules in order to understand how these molecular properties contribute to each molecule’s interaction with enzymes during each possible path of metabolism. We also apply correlated quantum mechanical methods, such as MP2, and DFT methods to the interaction of acetaminophen and its cresol analogs with the active site of uridine 5’-diphosphoglucuronosyltransferase (UGT) which is responsible for its main metabolic pathway. From these calculations we can determine the strength of the binding of the ligands in the enzyme active site; based on these results, we can offer an electronic level of explanation for the known interference of p-cresol in the metabolism of acetaminophen. Further, we can offer predictions on how o-cresol and m-cresol might interfere in the same metabolic pathway.