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Molecular Modeling of the Metabolism of Acetaminophen and
Hofto, Laura Rebecca
Hofto, Laura Rebecca
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Text, Chemistry, Department of, Student research, Honors papers
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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.
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Laura Rebecca Hoftogranted permission for the digitization of her paper. It was submitted by CD.