CVMD iMed DMPK, AstraZeneca R&D Mölnda l, 431 83 Mölndal, Sweden.
Chem Res Toxicol. 2013 Aug 19;26(8):1139-55. doi: 10.1021/tx400183y. Epub 2013 Jul 5.
While xenobiotic carboxylic acids (XCAs) have been studied extensively with respect to their enzymatic conversion to potentially reactive acyl glucuronides with implications to drug induced hepatotoxicity, the formation of xenobiotic-S-acyl-CoA thioesters (xenobiotic-CoAs) have been much less studied in spite of data indicating that such conjugates may be equally or more reactive than the corresponding acyl glucuronides. This review addresses enzymes and cell organelles involved in the formation of xenobiotic-CoAs, the reactivity of such conjugates toward biological macromolecules, and in vitro and in vivo methodology to assess consequences of such reactivity. Further, the propensity of xenobiotic-CoAs to interfere with endogenous lipid metabolism, e.g., inhibition of β-oxidation or depletion of the CoA or carnitine pools, adds to the complexity of the potential contribution of XCAs to hepatotoxicity by a number of mechanisms in addition to those in common with the corresponding acyl glucuronides. On the basis of our review of the literature on xenobiotic-CoA conjugates, there appear to be a number of gaps in our understanding of the bioactivation of XCA both with respect to the mechanisms involved and the experimental approaches to distinguish between the role of acyl glucuronides and xenobiotic-CoA conjugates. These aspects are focused upon and described in detail in this review.
尽管外源性羧酸（XCAs）在其酶促转化为具有潜在反应性的酰基葡萄糖醛酸方面已经得到了广泛的研究，这些酰基葡萄糖醛酸可能导致药物诱导的肝毒性，但外源性-S-酰基辅酶 A 硫酯（xenobiotic-CoAs）的形成却研究得很少，尽管有数据表明这些共轭物的反应性可能与相应的酰基葡萄糖醛酸相当或更高。本文综述了参与外源性-CoAs 形成的酶和细胞器、这些共轭物对生物大分子的反应性、以及评估这种反应性后果的体外和体内方法。此外，外源性-CoAs 倾向于干扰内源性脂质代谢，例如β-氧化的抑制或 CoA 或肉碱池的耗尽，除了与相应的酰基葡萄糖醛酸共同的机制外，通过多种机制增加了外源性羧酸对肝毒性的潜在贡献。根据我们对外源性-CoA 共轭物文献的综述，我们对外源性羧酸的生物活化的理解似乎存在一些空白，无论是在涉及的机制方面，还是在区分酰基葡萄糖醛酸和外源性-CoA 共轭物作用的实验方法方面。本文详细地聚焦和描述了这些方面。
