Acetaminophen and Isoniazid treatment leads to oxidative stress and cytotoxicity in cerebellar granule neurons possibly by CYP2E1 activation

Abstract

Increasing evidence suggests that brain cytochrome P450 (CYP) can contribute to the in situ metabolism of xenobiotics. Xenobiotics can be metabolized by CYPs into more reactive products that can induce cytotoxicity and cell death. In addition, normal CYP enzymatic activity produces reactive oxygen species (ROS) that contribute to cell damage through oxidative mechanisms. CYP2E1 is a CYP isoform that can generate ROS and induce cytotoxicity in multiple tissue types. The aim of this study was to determine whether neuronal CYP2E1 induction by isoniazid and acetaminophen and/or its metabolism can induce significant brain cell impairment. Exposure of primary cultured cerebellar granule neurons to isoniazid increased CYP2E1 expression, ROS production and cell death. These results were also observed with acetaminophen treatment. The oxidative stress and cytotoxicity observed with both treatments was attenuated by simultaneous exposure to 4‐methyl pyrazole and diallyl sulfide, which are CYP2E1 inhibitors, or to a mimetic of superoxide dismutase/catalase, Eukarion‐134. These results suggest that the induction and activity of brain CYP2E1 could represent a risk of in situ xenobiotic‐induced oxidative neuronal damage. This work was supported by Fundación Miguel Alemán A.C. and DGAPA‐UNAM (IN214908), the first author is supported by a CONACYT fellowship.