Integration and control of metabolism of boar taint compounds

这项研究旨在更全面地了解影响臭味化合物、臭味化合物和雄酮积累的因素，这些因素会导致未去势的公猪生产的猪肉中产生异味和异味(野猪污染)。公猪通常在很小的时候就被阉割，以防止野猪受到污染，但阉割引起了人们对动物福利的担忧，并降低了猪的生产效率。这项研究的结果可以用来开发控制野猪污染的替代方法，从而消除阉割。我们将研究不同的猪细胞色素P450(CYP450)酶在由色氨酸产生的肠道微生物群产生的臭鼬的代谢和清除中的作用。在一些公猪中，臭鼬在肝脏中的代谢受到损害，使大量的臭鼬积聚在脂肪组织中，造成公猪的污染。雄烯醇酮是由接近成熟的睾丸产生的，作为性信息素。它在肝脏中通过II相结合反应转化为硫代偶联物和葡萄糖醛酸苷，并在胆汁中排泄。我们最近已经证明，在饮食中加入非营养结合剂，如活性碳，可以降低雄烯酮的水平。这些化合物可能会阻止雄烯酮通过肠-肝循环从消化道重吸收，我们现在计划进行详细的研究来证实这一点。核受体CAR、PXR和FXR调节CYP450和II期酶的表达，我们计划表征它们在雄烯酮和Skatole代谢相关基因调控中的中心作用。我们还发现这些受体有几个剪接变异体，其中一些对野生型受体的活性产生戏剧性和特异性的显性正向或显性负向效应；我们计划研究这些效应背后的分子机制。这项工作将加深对如何控制野猪污染问题的理解，但猪不仅是一种有价值的食用动物，而且被认为是与人类相关的毒理学和药理学研究的优秀模型。

This research is designed to obtain a more complete understanding of factors affecting the accumulation of odorous compounds, skatole and androstenone, which cause off-odours and off-flavors (boar taint) in pork produced from uncastrated male pigs. Male pigs are routinely castrated at an early age to prevent boar taint, but castration raises concerns about animal welfare, as well as decreases the productivity of pig production. The results of this research could be used to develop alternative methods to control boar taint so that castration can be eliminated. We will study the role of different porcine cytochrome P450 (CYP450s) enzymes in the metabolism and clearance of skatole, which is produced by the gut microflora from tryptophan. In some male pigs, the hepatic metabolism of skatole in compromised, so that high levels of skatole accumulate in fatty tissue, resulting in boar taint. Androstenone is produced by the testis near maturity and acts as a sex pheromone. It is converted to sulphoconjugates and glucuronides by phase II conjugation reactions in the liver and excreted in the bile. We have recently shown that levels of androstenone can be reduced by including non-nutritive binding agents such as activated carbon in the diet. These compounds likely prevent the reabsorption of androstenone from the digestive tract via the enterohepatic circulation, and we now plan to carry out detailed studies to confirm this. The nuclear receptors CAR, PXR and FXR regulate the expression of CYP450s as well as phase II enzymes and we plan to characterize their central role in the regulation of genes that are involved in the metabolism of androstenone and skatole. We have also found that these receptors have several splice variants, and some of these produce dramatic and specific dominant positive or dominant negative effects on the activity of the wild type receptor; we plan to investigate the molecular mechanisms behind these effects. This work will develop a better understanding of how to control the problem of boar taint, but the pig is not only a valuable food animal but is also recognized as an excellent model for toxicological and pharmacological studies of relevance to humans.