Brunoldi Enrico M, Zanoni Giuseppe, Vidari Giovanni, Sasi Soumya, Freeman Michael L, Milne Ginger L, Morrow Jason D
Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Chem Res Toxicol. 2007 Oct;20(10):1528-35. doi: 10.1021/tx700231a. Epub 2007 Sep 14.
15-deoxy-Delta12,14-prostaglandin J2 (15-d-PGJ2) is a dehydration product of PGD2. This compound possesses a highly reactive polyunsaturated carbonyl moiety that is a substrate for Michael addition with thiol-containing biomolecules such as glutathione and cysteine residues on proteins. By reacting with glutathione and proteins, 15-d-PGJ2 is believed to exert potent biological activity. Despite the large number of publications that have ascribed bioactivity to this molecule, it is not known to what extent 15-d-PGJ2 is formed in vivo. Levels of free 15-d-PGJ2 measured in human biological fluids such as urine are low, and the biological importance of this compound has thus been questioned. Because of its reactivity, we hypothesized that 15-d-PGJ2 is present in vivo primarily as a Michael conjugate. Therefore, we undertook a detailed study of the metabolism of this compound in HepG2 cells that are known to metabolize other cyclopentenone eicosanoids. We report that HepG2 cells primarily convert 15-d-PGJ2 to a glutathione conjugate in which the carbonyl at C-11 is reduced to a hydroxyl. Subsequently, the glutathione portion of the molecule is hydrolyzed with loss of glutamic acid and glycine resulting in a cysteine conjugate. These findings confirm a general route for the metabolism of cyclopentenone eicosanoids in HepG2 cells and may pave the way for new insights regarding the formation of 15-d-PGJ2 in vivo.
15-脱氧-Δ12,14-前列腺素J2（15-d-PGJ2）是前列腺素D2的脱水产物。该化合物具有高度反应性的多不饱和羰基部分，是与含硫醇生物分子（如谷胱甘肽和蛋白质上的半胱氨酸残基）进行迈克尔加成的底物。通过与谷胱甘肽和蛋白质反应，15-d-PGJ2被认为具有强大的生物活性。尽管有大量文献将生物活性归因于该分子，但尚不清楚15-d-PGJ2在体内的形成程度。在人类生物体液（如尿液）中测得的游离15-d-PGJ2水平较低，因此该化合物的生物学重要性受到质疑。由于其反应性，我们推测15-d-PGJ2在体内主要以迈克尔共轭物的形式存在。因此，我们对该化合物在已知能代谢其他环戊烯酮类二十碳烯酸的HepG2细胞中的代谢进行了详细研究。我们报告称，HepG2细胞主要将15-d-PGJ2转化为一种谷胱甘肽共轭物，其中C-11位的羰基被还原为羟基。随后，该分子的谷胱甘肽部分水解，失去谷氨酸和甘氨酸，生成半胱氨酸共轭物。这些发现证实了HepG2细胞中环戊烯酮类二十碳烯酸代谢的一般途径，并可能为深入了解15-d-PGJ2在体内的形成提供新的思路。
