ATP‐binding cassette (Abc) transporters and cytoprotective genes respond differentially to a hepatotoxic dose of acetaminophen in male and female mouse brain

Abstract

The choroid plexus (CP) or blood‐cerebrospinal fluid barrier (BCSFB) and blood‐brain barrier (BBB) control the movement of drugs and metabolites between the brain and systemic circulation. Gender differences in drug excretion and detoxification mechanisms can affect therapeutic and toxic responses. For example, male mice are more susceptible to acetaminophen (APAP) induced hepatotoxicity. The Abc transporters and one of their transcription factors, nuclear factor erythroid‐2‐related factor (Nrf2), play roles in the susceptibility to APAP induced hepatotoxicity. Our aim was to examine gender differences in expression of Abc transporters, Nrf2 and related stress genes (NAD(P)H quionine oxidoreductase‐1, Nqo1, and heme oxigenase‐1, Ho‐1) in the brain and CP. We hypothesized that hepatic/renal gender‐specific patterns of these cytoprotective genes would also be present in the blood brain interfaces. In female mice, as compared to male, Abcc1‐2 and Abcc4 transporters are more strongly expressed brain, supporting our hypothesis. qRT‐PCR analysis revealed higher expression of Abcc1‐2 and Nrf2 in the female brain, but no differences in the CP. Abcc4, Ho‐1 and Nqo1 showed higher expression in female in both brain interfaces. These differences may contribute to APAP potential for neurotoxicity. We examined the differences in mRNA expression of cytoprotective genes at the brain interfaces of WT and Nrf2−/− mice following a hepatotoxic dose of APAP (400 mg/kg). APAP enhanced the expression of Abcc2 and Abcc4 in brains of male WT mice, but reduced the expression of these transporters in male Nrf2−/− mice. No changes were observed in the brains of either genotype of female mice. These data suggest that the expression of these transporters in the female mouse brain are not altered by a hepatotoxic dose of APAP and that transcription factors other than Nrf2 may be responsible for the regulation of Abc transporters in the female brain.Support or Funding InformationSupported by NSF and NIH