Research and Development of Liver Cytochrome p-450 Function Inspection Medicine by a ^<13>C-Breath Test

用Dellaria的恶嗪酮（由苯基溴乙酸酯和（S）-2-苯基甘氨醇制备）作为非手性甘氨酸等价物合成了_L-[3<-13>-^C]丙氨酸、_L-[<13>3-^ C]苯丙氨酸、_L-[3-^<13>C]酪氨酸、_L-[2-^<13>C]天冬氨酸和_L-[4-<13>^ C]赖氨酸、_L-[4-<13>^C]谷氨酸、_L-[4-^<13>C]谷氨酰胺、_L-[3-^<13>C]雷公藤红素、_L-[5'-^<13>C]和_L-[6'-^<13>C]雷公藤红素。恶嗪酮与[<13>4C]卤代烷或[4C<13>]恶嗪酮与卤代烷的烷基化以高非对映选择性实现。水解和除去烷基化恶嗪酮的手性助剂得到各种L-[^<13>C]氨基酸。肝脏疾病与芳香族氨基酸苯丙氨酸和酪氨酸的血浆浓度异常升高有关。肝脏是芳香酸代谢的主要场所，特别是苯丙氨酸羟基化为酪氨酸和进一步降解。我们研究了L-[1-^<13>C]苯丙氨酸呼气试验和L-[1-^<13>C]酪氨酸呼气试验对检测肝硬化患者肝损害的有用性。首先，比较了<13>L-[1-^<13>C]苯丙氨酸和L-[1-^<13>C]酪氨酸给药后^ CO_2排出的时间过程。两种呼气试验的峰值时间均为20分钟，但L-[1-^<13>C]酪氨酸呼气试验的峰值时间高于L-[1-^<13>C]苯丙氨酸呼气试验。然后将L-[1-^<13>C]苯丙氨酸呼气试验和L-[1-^<13>C]酪氨酸呼气试验的参数与生化肝功能检查值进行比较。这些参数与传统上被认为是肝细胞储备措施的几个肝脏血液检查值相关性很好。因此，L-[1-^<13>C]苯丙氨酸呼气试验和L-[1-^<13>C]酪氨酸呼气试验可用于评估肝功能障碍的程度和进展。

_L-[3^<-13>C]Alanine, _L-[3-^<13>C]phenylalanine, _L-[3-^<13>C]tyrosine, _L-[2-^<13>C]aspartic acid, and _L-[4-^<13>C]lysine, _L-[4-^<13>C]glutamic acid, _L-[4-^<13>C]glutamine, _L-[3-^<13>C]triptophan, _L-[5'-^<13>C] and _L-[6'-^<13>C]triptophan were synthesized using Dellaria's oxazinone, prepared from phenylbromoacetate and (S)-2-phenylglycinol, as achiral glycine equivalent. Alkylation of the oxazinone with [^<13>C]alkyl halide or the [^<13>C] oxazinone with alkyl halide was achieved with high diastereoselectivity. Hydrolysis and removal of chiral auxiliary of the alkylated oxazinone gave a variety of _L-[^<13>C]amino acid.Liver disease is associated with an abnormal elevation of the plasma concentrations of the aromatic amino acids phenylalanine and tyrosine. The liver is the main site of aromatic acid metabolism, particularly the hydroxylation of phenylalanine to tyrosine and further degradation. We have examined the usefulness of the _L-[1-^<13>C]phenylalanine breath test and _L-[1-^<13>C]tyrosine breath test for the detection of hepatic damage in patients with liver cirrhosis. First, the time course of ^<13>CO_2 excretion after the administration of _L-[1-^<13>C]phenylalanine and _L-[1-^<13>C]tyrosine were compared. The peak times were 20 min. in both breath test, but _L-[1-^<13>C]tyrosine breath test gave a higher peak than _L-[1-^<13>C]phenylalanine breath test. Next the parameter of _L-[1-^<13>C]phenylalanine breath test and _L-[1-^<13>C]tyrosine breath test were compared with biochemical liver function test values. These parameters were well correlated with several liver blood test values conventionally regarded as measures of hepatocyte reserve. Therefore, _L-[1-^<13>C]phenylalanine breath test and _L-[1-^<13>C]tyrosine breath test may be useful to assess the degree and progression of hepatic dysfunctions.