Jack Uetrecht

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Hepatic inflammation is a common finding during a variety of liver diseases including drug-induced liver toxicity. The inflammatory phenotype can be attributed to the innate immune response generated by Kupffer cells, monocytes, neutrophils, and lymphocytes. The adaptive immune system is also influenced by the innate immune response leading to liver damage.(More)
Clinical characteristics and circumstantial evidence suggest that idiosyncratic drug reactions are caused by reactive metabolites and are immune-mediated; however, there are few definitive data and there are likely exceptions. There are three principal hypotheses for how reactive metabolites might induce an immune-mediated idiosyncratic reaction: the hapten(More)
Diclofenac is associated with a low, but significant, incidence of hepatotoxicity and bone marrow toxicity. It has been suggested that this could be due to a reactive acyl glucuronide. An alternative hypothesis is that an oxidative reactive metabolite could be responsible for such reactions and such metabolites formed by the enzymes present in neutrophils(More)
The reverse transcriptase inhibitor, nevirapine (NVP), causes skin rashes and hepatotoxicity. We used a rat model to determine if the rash is caused by the parent drug or a reactive metabolite. By manipulation of metabolic pathways and testing analogues, we eliminated all but one pathway, 12-hydroxylation, which involves the oxidation of an exocyclic methyl(More)
Clozapine was oxidized to a reactive intermediate by HOCI, which is the major oxidant produced by activated neutrophils. A mass spectrum was obtained of this reactive intermediate by using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a Sciex API III mass spectrometer. The intermediate was observed(More)
OBJECTIVES To determine, first, whether the plasma and lymphocytes of HIV-positive individuals and AIDS patients have alterations in the major thiols glutathione and cysteine, and/or their oxidative disulphide and mixed disulphide products; and, secondly, whether thiol/disulphide status differs in patients with sulphonamide drug hypersensitivity reactions.(More)
Many adverse drug reactions are mediated by the immune system. This can be because the therapeutic effect of the drug targets the immune system. For example, immunosuppressive drugs increase the risk of infections. It is paradoxical that some immunosuppressive drugs can lead to autoimmune reactions. Another mechanism by which drugs can cause an adverse(More)
STUDY OBJECTIVE To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents. DESIGN In-vitro toxicity assay on lymphocytes. SETTING(More)