Molecular pharmacology
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Molecular pharmacology · Sep 1996
Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis.
Recent studies have shown that cytochrome P450 2E1 (CYP2E1) is a major catalyst of formation of trifluoroacetylated proteins, which have been implicated as target antigens in the mechanism of halothane hepatitis. In the present investigation, trifluoroacetylated CYP2E1 was detected immunochemically in livers of rats treated with halothane. Furthermore, high levels of autoantibodies that recognized purified rat CYP2E1 but not purified rat CYP3A were detected by enzyme-linked immunosorbent assay in 14 of 20 (70%) sera from patients with halothane hepatitis. ⋯ A very similar distribution was found for CYP2E1 in FGC4 cells, and immunoprecipitation experiments performed in cultures of FGC4-related Fao hepatoma cells suggest that surface immunoreactivity originates from a small fraction of intact CYP2E1 apoprotein. Human CYP2E1, expressed in V79 cells after cDNA transfection, was also detected to a minor extent in the plasma membrane, whereas no immunofluorescence was evident in parental V79 cells. It is suggested that immune responses to cell surface CYP2E1 could be involved in the pathogenesis of halothane hepatitis.
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Molecular pharmacology · Sep 1996
The mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) [but not D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP)] produces a nonopioid receptor-mediated increase in K+ conductance of rat locus ceruleus neurons.
The somatostatin analogues D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) have been used widely as selective antagonists of mu-opioid receptors. Actions of CTOP and CTAP on the membrane properties of rat locus ceruleus neurons were studied using intracellular recordings of membrane currents in superfused brain slices. CTOP increased a K+ conductance with an EC50 of 560 nM. ⋯ CTAP did not antagonize K+ currents produced by CTOP or somatostatin. These results demonstrate that CTOP is a potent and efficacious agonist at nonopioid receptors, whereas CTAP is a potent mu-opioid receptor antagonist with little nonopioid agonist activity in rat locus ceruleus neurons. The receptor activated by CTOP has yet to be fully resolved but seems to be similar to the somatostatin type 2 receptor or perhaps to a receptor closely related to somatostatin or opioid receptors.