Sex-Specific Modulation of Drug Metabolizing Enzymes, Transporters, and Pro-Inflammatory Cytokines by Arsenic Trioxide in C57Bl/6 Mice

Abstract

Arsenic trioxide (ATO) is both a life-saving therapy for acute promyelocytic leukemia and a systemic toxicant whose hepatic effects remain incompletely defined. This study examined how a single clinically relevant ATO dose (8 mg/kg, i.p.) acutely remodels hepatic xenobiotic-metabolizing enzymes, arsenic transporters, and pro-inflammatory mediators in male and female C57Bl/6 mice. Mice were treated with ATO or saline and livers were collected at 6 and 24 h for integrated mRNA and protein profiling of major Cytochrome P450 (CYP) families, aquaglyceroporins (Aqp3/7/9), ATP-binding cassette (Abcb1, Abcc1–6) transporters, and cytokines (Tnf-α, Il-1β, Il-6). ATO induced highly sex-, time-, and isoform-specific reprogramming. Females exhibited a wider and earlier decline in several female-predominant CYP2, CYP3, and CYP4 isoforms, including a more pronounced reduction in hepatic CYP3A, CYP4A, and CYP4F protein abundance. In contrast, males showed mainly transcriptional induction of specific genes (Cyp1a1, Cyp2a, Cyp3a13, and Cyp4a), accompanied by comparatively modest decreases in overall CYP protein levels. Aqp and Abc transporters were differentially modulated, with males displaying early, relatively monotonic upregulation of Abcb1/Abcc efflux systems, while females exhibited higher basal Abc expression but more complex, biphasic regulation of both influx (Aqp7/9) and efflux pathways. These transcriptional changes paralleled a transient inflammatory response, including early Tnf-α induction and female-specific Il-6 elevation. Collectively, these findings highlight sex-dependent modulation of hepatic ATO handling and drug metabolizing capacity, with important implications for risk assessment and individualized ATO containing regimens.