Bigelow S W, Collins A C, Nebert D W
Laboratory of Developmental Pharmacology, National Institute of Child Health and Human Development, Bethesda, MD 20892.
Biochem Pharmacol. 1989 Oct 15;38(20):3565-72. doi: 10.1016/0006-2952(89)90129-9.
Following a selective breeding program of heterogeneous mice for more than 30 generations, SS ("short sleep") and LS ("long sleep") lines have been developed on the basis of their sleep times when challenged with a single intraperitoneal dose of ethanol. The aromatic hydrocarbon responsiveness (Ah) locus encodes the Ah receptor, which regulates the induction of certain drug-metabolizing enzymes by polycyclic aromatic compounds such as 3-methylcholanthrene and tetrachlorodibenzo-p-dioxin. The C57BL/6 inbred mouse strain (B6; Ahb/Ahb) has a high-affinity Ah receptor, while the DBA/2 inbred mouse strain (D2; Ahd/Ahd) has a low-affinity Ah receptor. We show here that the SS inbred mouse line exhibits markedly elevated hepatic levels of the high-affinity Ah receptor, while the LS outbred mouse line contains the low-affinity Ah receptor. Among progeny of (B6D2)F1 X D2 backcross, the b/d heterozygote (having the high-affinity Ah receptor) was found to be several times more resistant than the d/d homozygote to a single dose of intraperitoneal ethanol. The D2.B6-Ahb congenic line is also several times more resistant to intraperitoneal ethanol than the B6.D2-Ahb congenic line is also several times more resistant to intraperitoneal ethanol than B6.D2-Ahd congenic line. We found that the waking blood ethanol levels are the same in b/d and d/d mice, suggesting that the relative ethanol resistance in b/d mice cannot be explained on the basis of a difference in central nervous system sensitivity. There are no differences between SS and LS mice or between b/d and d/d mice with regard to (i) blood acetaldehyde levels after a single intraperitoneal dose of ethanol, or (ii) hepatic alcohol dehydrogenase activities. There is a difference in the rate of ethanol elimination: SS more rapid than LS; b/d more rapid than d/d. Although SS mice have lower hepatic aldehyde dehydrogenase activities (cytosolic, mitochondrial low-Km: and mitochondrial high-Km forms) than LS mice, b/d and d/d do not show this difference. These data suggest that a selected mouse breeding program, based on resistance to a single intraperitoneal dose of ethanol, selects concurrently for the hepatic high-affinity Ah receptor. This selective advantage cannot be explained on the basis of changes in alcohol dehydrogenase or aldehyde dehydrogenase activities and might provide insight into the nature of the endogenous ligand for the Ah receptor.
经过30多代对异质小鼠的选择性育种计划，已根据单次腹腔注射乙醇后小鼠的睡眠时间培育出了SS（“短睡眠”）和LS（“长睡眠”）品系。芳烃反应性（Ah）位点编码Ah受体，该受体调节某些药物代谢酶的诱导，这些酶由多环芳烃化合物如3-甲基胆蒽和四氯二苯并对二恶英诱导产生。C57BL/6近交系小鼠品系（B6；Ahb/Ahb）具有高亲和力的Ah受体，而DBA/2近交系小鼠品系（D2；Ahd/Ahd）具有低亲和力的Ah受体。我们在此表明，SS近交系小鼠品系肝脏中高亲和力Ah受体水平显著升高，而LS远交系小鼠品系含有低亲和力的Ah受体。在（B6D2）F1与D2回交的后代中，发现b/d杂合子（具有高亲和力Ah受体）对单次腹腔注射乙醇的抗性比d/d纯合子高几倍。D2.B6-Ahb同源系对腹腔注射乙醇的抗性也比B6.D2-Ahb同源系高几倍，B6.D2-Ahd同源系对腹腔注射乙醇的抗性也比B6.D2-Ahd同源系高几倍。我们发现b/d和d/d小鼠清醒时的血液乙醇水平相同，这表明b/d小鼠相对的乙醇抗性不能基于中枢神经系统敏感性的差异来解释。在单次腹腔注射乙醇后，SS和LS小鼠之间或b/d和d/d小鼠之间在（i）血液乙醛水平或（ii）肝脏乙醇脱氢酶活性方面没有差异。乙醇消除速率存在差异：SS比LS快；b/d比d/d快。尽管SS小鼠的肝脏醛脱氢酶活性（胞质、线粒体低Km和线粒体高Km形式）低于LS小鼠，但b/d和d/d之间没有这种差异。这些数据表明，基于对单次腹腔注射乙醇的抗性进行的小鼠选育计划同时选择了肝脏中的高亲和力Ah受体。这种选择优势不能基于乙醇脱氢酶或醛脱氢酶活性的变化来解释，并且可能为Ah受体的内源性配体的性质提供见解。
