Departments of Pharmaceutics (L.W.H., Q.M.) and Medicinal Chemistry (Y.S.), School of Pharmacy, Departments of Environmental and Occupational Health Sciences, School of Public Health (L.W., J.L.D., M.D., T.K.B., J.Y.C.), and Department of Comparative Medicine, School of Medicine (O.V.P.), University of Washington, Seattle, Washington.
Departments of Pharmaceutics (L.W.H., Q.M.) and Medicinal Chemistry (Y.S.), School of Pharmacy, Departments of Environmental and Occupational Health Sciences, School of Public Health (L.W., J.L.D., M.D., T.K.B., J.Y.C.), and Department of Comparative Medicine, School of Medicine (O.V.P.), University of Washington, Seattle, Washington
Drug Metab Dispos. 2020 Aug;48(8):708-722. doi: 10.1124/dmd.120.000039. Epub 2020 Jun 4.
The microbiome and pregnancy are known to alter drug disposition, yet the interplay of the two physiologic factors on the expression and/or activity of drug metabolizing enzymes and transporters (DMETs) is unknown. This study investigated the effects of microbiome on host hepatic DMETs in mice during pregnancy by comparing four groups of conventional (CV) and germ-free (GF) female mice and pregnancy status, namely, CV nonpregnant, GF non-pregnant, CV pregnant, and GF pregnant mice. Transcriptomic and targeted proteomics of hepatic DMETs were profiled by using multiomics. Plasma bile acid and steroid hormone levels were quantified by liquid chromatography tandem mass spectrometry. CYP3A activities were measured by mouse liver microsome incubations. The trend of pregnancy-induced changes in the expression or activity of hepatic DMETs in CV and GF mice was similar; however, the magnitude of change was noticeably different. For certain DMETs, pregnancy status had paradoxical effects on mRNA and protein expression in both CV and GF mice. For instance, the mRNA levels of , the murine homolog of human , were decreased by 1.7-fold and 3.3-fold by pregnancy in CV and GF mice, respectively; however, the protein levels of CYP3A11 were increased similarly ∼twofold by pregnancy in both CV and GF mice. Microsome incubations revealed a marked induction of CYP3A activity by pregnancy that was 10-fold greater in CV mice than that in GF mice. This is the first study to show that the microbiome can alter the expression and/or activity of hepatic DMETs in pregnancy. SIGNIFICANCE STATEMENT: We demonstrated for the first time that microbiome and pregnancy can interplay to alter the expression and/or activity of hepatic drug metabolizing enzymes and transporters. Though the trend of pregnancy-induced changes in the expression or activity of hepatic drug metabolizing enzymes and transporters in conventional and germ-free mice was similar, the magnitude of change was noticeably different.
微生物组和妊娠已知会改变药物处置，但这两个生理因素对药物代谢酶和转运体（DMETs）的表达和/或活性的相互作用尚不清楚。本研究通过比较四组常规（CV）和无菌（GF）雌性小鼠和妊娠状态，即 CV 未怀孕、GF 未怀孕、CV 怀孕和 GF 怀孕小鼠，研究了微生物组对妊娠期间宿主肝 DMETs 的影响。使用多组学对肝 DMETs 的转录组和靶向蛋白质组进行了分析。通过液相色谱串联质谱法定量测定血浆胆汁酸和类固醇激素水平。通过小鼠肝微粒体孵育测量 CYP3A 活性。CV 和 GF 小鼠中妊娠诱导的肝 DMETs 表达或活性变化的趋势相似；然而，变化的幅度明显不同。对于某些 DMETs，妊娠状态对 CV 和 GF 小鼠的 mRNA 和蛋白质表达具有相反的影响。例如，在 CV 和 GF 小鼠中，妊娠使 的 mRNA 水平分别降低了 1.7 倍和 3.3 倍；然而，CYP3A11 的蛋白水平在 CV 和 GF 小鼠中均相似地增加了约 2 倍。微体孵育显示，妊娠明显诱导 CYP3A 活性，CV 小鼠中的诱导作用比 GF 小鼠中的诱导作用高 10 倍。这是第一项表明微生物组可以改变妊娠期间肝 DMETs 的表达和/或活性的研究。意义声明：我们首次证明微生物组和妊娠可以相互作用改变肝药物代谢酶和转运体的表达和/或活性。尽管常规和无菌小鼠中妊娠诱导的肝药物代谢酶和转运体表达或活性变化的趋势相似，但变化的幅度明显不同。
