Holowiecki Andrew, O'Shields Britton, Jenny Matthew J
Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA; Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, OH, USA.
Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA.
Toxicol Appl Pharmacol. 2016 Nov 15;311:74-87. doi: 10.1016/j.taap.2016.09.022. Epub 2016 Sep 23.
While heme is an important cofactor for numerous proteins, it is highly toxic in its unbound form and can perpetuate the formation of reactive oxygen species. Heme oxygenase enzymes (HMOX1 and HMOX2) degrade heme into biliverdin and carbon monoxide, with biliverdin subsequently being converted to bilirubin by biliverdin reductase (BVRa or BVRb). As a result of the teleost-specific genome duplication event, zebrafish have paralogs of hmox1 (hmox1a and hmox1b) and hmox2 (hmox2a and hmox2b). Expression of all four hmox paralogs and two bvr isoforms were measured in adult tissues (gill, brain and liver) and sexually dimorphic differences were observed, most notably in the basal expression of hmox1a, hmox2a, hmox2b and bvrb in liver samples. hmox1a, hmox2a and hmox2b were significantly induced in male liver tissues in response to 96h cadmium exposure (20μM). hmox2a and hmox2b were significantly induced in male brain samples, but only hmox2a was significantly reduced in male gill samples in response to the 96h cadmium exposure. hmox paralogs displayed significantly different levels of basal expression in most adult tissues, as well as during zebrafish development (24 to 120hpf). Furthermore, hmox1a, hmox1b and bvrb were significantly induced in zebrafish eleutheroembryos in response to multiple pro-oxidants (cadmium, hemin and tert-butylhydroquinone). Knockdown of Nrf2a, a transcriptional regulator of hmox1a, was demonstrated to inhibit the Cd-mediated induction of hmox1b and bvrb. These results demonstrate distinct mechanisms of hmox and bvr transcriptional regulation in zebrafish, providing initial evidence of the partitioning of function of the hmox paralogs.
虽然血红素是众多蛋白质的重要辅因子，但其游离形式具有高毒性，可促使活性氧的形成。血红素加氧酶（HMOX1和HMOX2）将血红素降解为胆绿素和一氧化碳，随后胆绿素由胆绿素还原酶（BVRa或BVRb）转化为胆红素。由于硬骨鱼特有的基因组复制事件，斑马鱼有hmox1（hmox1a和hmox1b）和hmox2（hmox2a和hmox2b）的旁系同源基因。在成年组织（鳃、脑和肝脏）中检测了所有四个hmox旁系同源基因和两个bvr亚型的表达，并观察到性别二态性差异，最显著的是在肝脏样本中hmox1a、hmox2a、hmox2b和bvrb的基础表达。在暴露于96小时镉（20μM）后，雄性肝脏组织中hmox1a、hmox2a和hmox2b显著诱导。在雄性脑样本中hmox2a和hmox2b显著诱导，但在暴露于96小时镉后，仅雄性鳃样本中hmox2a显著降低。hmox旁系同源基因在大多数成年组织以及斑马鱼发育过程（24至120小时胚胎期）中表现出显著不同的基础表达水平。此外，在斑马鱼胚胎中，多种促氧化剂（镉、血红素和叔丁基对苯二酚）可显著诱导hmox1a、hmox1b和bvrb。已证明敲低hmox1a的转录调节因子Nrf2a可抑制镉介导的hmox1b和bvrb诱导。这些结果证明了斑马鱼中hmox和bvr转录调控的不同机制，为hmox旁系同源基因功能划分提供了初步证据。
