Fig 1: Changes in phase I and II genes in cholestatic mice result in protection against zoxazolamine and acetaminophen (APAP) toxicity.(A) Double-knockout (DKO) cholestatic livers show increased immunofluorescence staining for CYP2B6 compared with wild-type (WT) livers (n = 4–5 mice per group; scale bar: 50 µm). (B) Bar graph indicates that DKO mice recover faster post zoxazolamine (zox)-induced paralysis than WT mice. Inhibiting constitutive androstane receptor activity with androstanol normalises the difference in paralysis time between WT and DKO mice (n = 3–4 mice per group; mean ± SEM; one-way ANOVA; **p <0.01). (C) Schematic of acetaminophen metabolism in the liver. (D and E) qPCR analysis shows upregulation of key genes involved in APAP metabolism in DKO livers (n = 4–6 mice per group; Student's t test; *p <0.05). (F) Hepatic glutathione disulphide (GSH) levels at different time points post-APAP treatment in control WT and cholestatic DKO mice. (G) Histological analysis of liver sections at 0, 6, and 24 h after APAP injection shows reduced necrosis in the DKO compared with WT mice (n = 4–6 mice per group; mean ± SEM; one-way ANOVA; *p <0.05, **p <0.01, ***p <0.005, ****p <0.001).