Integration and control of metabolism of boar taint compounds

本研究旨在更全面地了解影响恶臭化合物、粪臭素和雄烯酮积累的因素，这些化合物会导致未阉割的公猪生产的猪肉产生异味和异味（公猪粪臭）。为了防止公猪受到污染，通常会在很小的时候对公猪进行阉割，但阉割会引起对动物福利的担忧，并降低猪的生产效率。本研究结果可用于开发控制公猪污染的替代方法，从而消除阉割。我们将研究不同的猪细胞色素P450 （cyp450）酶在粪臭素代谢和清除中的作用，粪臭素是由肠道菌群由色氨酸产生的。在一些公猪中，粪臭素的肝脏代谢受到损害，使高水平的粪臭素积聚在脂肪组织中，导致公猪粪臭。雄烯酮是由接近成熟的睾丸产生的，作为一种性信息素。它在肝脏中通过II相偶联反应转化为硫偶联物和葡萄糖醛酸盐，并通过胆汁排出体外。我们最近的研究表明，通过在饮食中加入非营养性的结合剂，如活性炭，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新吸收，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以及II期酶的表达，我们计划描述它们在调节参与雄烯酮和臭臭素代谢的基因中的核心作用。我们还发现这些受体有几个剪接变体，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积极或显性消极影响；我们计划研究这些效应背后的分子机制。这项工作将使人们更好地了解如何控制猪粪污染问题，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.