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. 2022 Nov 22;130(2):154–164. doi: 10.1016/j.bja.2022.09.025

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Fig 3 — Sex-specific metabolism modulates hypnotic effect of 3β-OH. We harvested tissue samples after administration of 100 mg kg⁻¹ of 3β-OH i.p. and measured steroid concentration using HPLC-MS/MS as indicated by cartoon inset on the right (brain and liver, n=2–3 at 0 min and n=5–6 at 10–720 min; plasma and urine, n=1–3 at 0 and 720 min and n=4–6 at 10–540 min). (a–d) In brain, liver, plasma, and urine, concentration of 3β-OH changed across different time points (two-way anova sex by time-point, Sidak's multiple comparisons: F_11,108=48.170, P<0.0001; F_11,108=16.242, P<0.0001; F_1,104=29.355, P<0.0001; F_11,94=2.114, P=0.026, respectively). (a) In brain, males had higher 3β-OH concentrations than females (F_1,108=12.902, ∗∗∗∗P<0.0001; inset) and the interaction showed that this was specific to 30 (∗P=0.003) min after injection. (b) Males also had higher 3β-OH concentrations in liver (F_1,108=9.103, ∗∗∗P=0.003; inset) but no significant interaction. (c) Plasma samples showed no sex effects. (d) In urine, females had higher 3β-OH concentrations compared with males (F_1,94=24.982, ∗∗∗∗P<0.0001; inset). (e) Scheme shows that 3β-OH is metabolised into 3α-OH by 3α-HSD in a reversible reaction. (f–i) We found that after injections of 3β-OH i.p., concentrations of 3α-OH changed across different time points in brain, liver, plasma, and urine (F_11,108=11.757, P<0.0001; F_11,108=10.623, P<0.0001; F_11,104=8.911, P<0.0001; F_11,94=2.462, P=0.009, respectively). (f) For brain concentrations, females had higher 3α-OH concentrations compared with males (F_1,108=85.652, ∗∗∗∗P<0.0001; inset). There was also a significant interaction (F_11,108=3.161, P=0.001) showing that this was specific to 40 (∗P<0.0001), 80 (∗P<0.0001), 120 (∗P<0.001), and 180 (∗P<0.0001) min after injection. (g) Females also had higher 3α-OH in liver compared with males (F_11,108=64.689, ∗∗∗∗P<0.0001; inset). (h) Similarly, in plasma, females had higher 3α-OH concentrations compared with males (F_1,104=83.985, ∗∗∗∗P<0.0001; inset), and there was a significant interaction (F_11,104=3.703, P<0.0001), indicating this was specific to 20 (∗P=0.049), 80 (∗P=0.019), 120 (∗P=0.012), and 180 (∗P<0.0001) min after injection of 3β-OH. (i) Females excreted 3α-OH in urine at higher concentrations than males (F_1,94=37.160, ∗∗∗∗P<0.0001; inset), and there was no significant interaction. 3β-OH, (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile; LORR, loss of righting reflex; HPLC-MS/MS, high-performance liquid chromatography coupled to tandem mass spectrometry; 3α-OH, (3α,5β,17β)-3-hydroxyandrostane-17-carbonitrile; 3α-HSD, 3α-hydroxysteroid dehydrogenase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; anova, analysis of variance.