Abstract
Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase–mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgammanull mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity.
SIGNIFICANCE STATEMENT High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.
Footnotes
- Received June 1, 2023.
- Accepted October 13, 2023.
Services and products in support of the research project were generated by the Virginia Commonwealth University Flow Cytometry; Cancer Mouse Models; Microscopy Shared Resource, supported, in part, with funding from a National Institutes of Health National Cancer Institute Cancer Center support grant [Grant P30CA016059]; the Analytical Core at KUMC, supported, in part, by a National Institute of General Medicine–funded Liver Disease COBRE grant [Grant P30GM118247] (to H.J.). The work was supported by a Swim Across America grant; VA [Grant 5IK2BX004914-02] (to A.N.); and a VCU Internal Medicine Seed Grant.
Department of Veterans Affairs (A.N. and A.B.) has a patent pending for concurrent use of CYP2E1 inhibitors and acetaminophen.
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