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Acetaminophen analog N-acetyl-m-aminophenol, but not its reactive metabolite, N-acetyl-p-benzoquinone imine induces CYP3A activity via inhibition of protein degradation. | LitMetric

AI Article Synopsis

  • Cytochrome P450 (CYP) 3A enzymes play a crucial role in drug metabolism, and understanding their regulation is essential for predicting drug-drug interactions (DDIs).
  • Previous research indicated that acetaminophen (APAP) enhances CYP3A activity by preventing protein degradation, leading to questions about the role of its reactive metabolite, NAPQI.
  • Experiments with different APAP analogs showed that while N-acetyl-m-aminophenol (AMAP) inhibits CYP3A protein degradation, p-acetamidobenzoic acid (PAcBA) does not, suggesting that chemical structure influences the impact on CYP3A regulation.

Article Abstract

Cytochrome P450 (CYP) 3A subfamily members are known to metabolize various types of drugs, highlighting the importance of understanding drug-drug interactions (DDI) depending on CYP3A induction or inhibition. While transcriptional regulation of CYP3A members is widely understood, post-translational regulation needs to be elucidated. We previously reported that acetaminophen (APAP) induces CYP3A activity via inhibition of protein degradation and proposed a novel DDI concept. N-Acetyl-p-benzoquinone imine (NAPQI), the reactive metabolite of APAP formed by CYP, is known to cause adverse events related to depletion of intracellular reduced glutathione (GSH). We aimed to inspect whether NAPQI rather than APAP itself could cause the inhibitory effects on protein degradation. We found that N-acetyl-l-cysteine, the precursor of GSH, and 1-aminobenzotriazole, a nonselective CYP inhibitor, had no effect on CYP3A1/23 protein levels affected by APAP. Thus, we used APAP analogs to test CYP3A1/23 mRNA levels, protein levels, and CYP3A activity. We found N-acetyl-m-aminophenol (AMAP), a regioisomer of APAP, has the same inhibitory effects of CYP3A1/23 protein degradation, while p-acetamidobenzoic acid (PAcBA), a carboxy-substituted form of APAP, shows no inhibitory effects. AMAP and PAcBA cannot be oxidized to quinone imine forms such as NAPQI, so the inhibitory effects could depend on the specific chemical structure of APAP.

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Source
http://dx.doi.org/10.1016/j.bbrc.2017.03.073DOI Listing

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