Biology subjects

Akakpo, J. Y.

Publications and source records attributed to Akakpo, J. Y..

2 recordsLinked to original sources

bioRxiv2026

Dysregulation of xenobiotic metabolism and mitochondrial dysfunction exacerbate acetaminophen-induced hepatotoxicity in human antigen R-deficient male mice

Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide. The RNA-binding protein Human antigen R (HuR) is a multifunctional post-transcriptional regulator that plays a pivotal role in cellular stress responses, including those triggered by APAP toxicity. This study investigated the mechanisms by which HuR protects against APAP-induced hepatotoxicity in male mice. Hepatocyte-specific HuR-deficient (HuRHep-/-) male mice on a C57BL/6N background and wild-type (WT) littermates were treated with 200 mg/kg APAP, and liver tissues were collected at 2, 6, and 24 hours post-treatment. APAP administration increased hepatic HuR mRNA expression and induced HuR cleavage and the formation of a higher-molecular weight HuR-immunoreactive band, with the latter two correlating with injury severity. Compared with WT controls, HuRHep-/- mice exhibited markedly increased susceptibility to hepatotoxicity at both 2 and 6 hours. Metabolite profiling revealed altered APAP metabolism and reduced glutathione S-transferase (Gst) expression in HuRHep-/- livers, consistent with impaired APAP detoxification and increased APAP-protein adduct formation. Fourier-transform infrared (FTIR) spectroscopy further identified early biochemical differences between WT and HuRHep-/- livers as early as 2 hours after APAP exposure. Additionally, HuR deficiency resulted in pronounced mitochondrial structural abnormalities and dysfunction at 2 and 6 hours, accompanied by reduced expression of the mitochondrial fission and fusion proteins Drp1 and Mfn2, increased mitochondrial protein release, and enhanced hepatocyte death. Although pro-inflammatory cytokine levels were elevated in HuRHep-/- mice relative to WT controls at 24 hours, hepatocyte proliferation was similarly blunted in both genotypes, consistent with severe liver injury and delayed recovery. Collectively, these findings identify hepatocyte HuR as a critical regulator of xenobiotic metabolism and mitochondrial integrity and establish its essential role in early protection against APAP-induced hepatotoxicity in male mice.

pharmacology and toxicology↗

bioRxiv2024

Sex-dependent effects of CYP2E1 on the kidney and the protective potential of 4MP against cisplatin-induced nephrotoxicity

Cisplatin is an effective chemotherapeutic drug for the treatment of bladder cancer, though cisplatin-induced nephrotoxicity (CIN) occurs in approximately 20-30% of patients, limiting its clinical use. Evidence has shown that cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme expressed in proximal tubules, mediates the production of reactive oxygen species (ROS) during cisplatin-induced injury. Previously, we showed that the repurposed drug 4-methylpyrazole (4MP; fomepizole) blocks CYP2E1 activity and prevents acetaminophen-induced liver injury. Here, we investigated the potential protective effects of 4MP against CIN. Male and female C57BL/6J mice were treated with a single 20 mg/kg dose of cisplatin for 3 days (acute) or 9 mg/kg/week for 4 weeks (repeated dosing regimen) with or without 50 mg/kg 4MP as a co-treatment. Our findings revealed that acute treatment with cisplatin induced severe histological tubular damage and elevated plasma BUN and creatinine levels in male mice, but not in female mice. This difference correlated with higher basal CYP2E1 expression in the kidneys of male mice compared to female mice. We also found that cisplatin increased renal CYP2E1 activity and that inhibition of CYP2E1 with 4MP significantly reduced cisplatin induced cell death in male mice and primary normal human kidney cells. By contrast, human bladder cancer cells do not express CYP2E1, and treatment with 4MP did not interfere with cisplatins anti-cancer effects in human bladder cancer HTB9 cells. This study highlights the critical role of CYP2E1 in CIN and suggests that its inhibition with 4MP in the kidney is a potential prophylactic therapeutic option to prevent CIN in bladder cancer patients without affecting its anti-neoplastic effect. Impact StatementThis study demonstrates that cytochrome P450 2E1 (CYP2E1) is a critical mechanistic target in the prevention of cisplatin-induced nephrotoxicity (CIN). It also indicates that CYP2E1 plays an important role in mediating sex-specific differences in CIN. Finally, this study reveals that targeting CYP2E1 with 4methylpyrazole offers a promising prophylactic approach to reducing CIN in clinical settings while preserving the anti-cancer efficacy of cisplatin.

pharmacology and toxicology↗