(A) Gene expression within the reconstituted ‘humanized liver’ of TK-NOG mice. Global gene expression profiles within a fully humanized TK-NOG liver (RI of >85%) and donor human liver cells were compared by microarray analysis. The blue and black triangles indicate ‘absent or marginal’ and ‘present’ detection calls, respectively. The red circles indicate the probe sets for mRNAs related to drug metabolism. (B) The relative expression of 26 human drug metabolism related mRNAs in four independent ‘humanized’ TK-NOG livers and in donor human liver cells (nHeps) was assessed by qPCR. Each bar represents the average of 3 independent determinations and the standard error is shown. (C) Human (CYP2D6)-specific drug biotransformation in humanized TK-NOG mice. The serum concentration of DEB (left panel) and 4-OH DEB (right panel) in control NOG (n = 9) and humanized TK-NOG (n = 6) mice were measured 0, 0.5, 1, 2, 4 and 7 hrs after administration of a single oral dose of DEB (2 mg/kg). Each data point represents the average ± SD of 6-9 independent mice tested. (D) Urine samples were collected between 0 and 7 hrs after DEB administration. The % ratio of 4-OH DEB/DEB excreted into urine within 7 hr was compared between control NOG (n = 9) and humanized TK-NOG mice (n = 6). By all of these measures, humanized TK-NOG mice had significantly increased amounts of 4-OH DEB in the plasma and higher 4-OH DEB excretion than control NOG mice.