Metabolic Characteristics and Enflurane Defluorination of Cytochrome P450-Dependent Monooxygenases in Human Hepatocellular Carcinoma

人類肝細胞癌細胞色素P450單氧酵素系統代謝特性及Enflurane去氟化之研究

陳大樑(Ta-Liang Chen) ； 侯文詠(Wen-Yeong Hou) ； 孫維仁(Wei-Zen Sun) ； 吳鋼治(Gong-Jhe Wu) ； 王國清(Kuo-Ching Wang) ； 彭文玲(Wen-Ling Peng) ； 林珍榮(Chen-Jung Lin)

《Acta Anaesthesiologica Sinica》 35卷1期 (1997/03) Pp. 7-14

摘要

Background: Xenobiotic metabolism and defluorination capacity of microsomal monooxygenases were investigated in vitro through the surgical specimens of liver resected from patients with hepatocellular carcinoma and patients of extrahepatic pathology as control. Methods: In microsomes of hepatocellular carcinoma tissues, the activities of cytochrome P450-dependent monooxygenase isozymes 1A1, 2B1, and 2E1 were evaluated in vitro by reacting with the specific marker substrates benzo(a)pyrene, benzphetamine and aniline, respectively, in the generating incubation system. The distant normal liver tissues and tissues from control patients with extrahepatic lesion were also investigated for comparison. The ability of enflurane defluorination was assessed by Orion combined electrode for detection of free fluoride ion production. Results: Concentrations of P450 total content, cytochrome b_5, and NADPH-cytochrome c reductase showed parallel and marked reduction in tumor tissues when compared with its distant normal regions or normal livers. The monooxygenase functions displayed significant decreases within the tumor tissues as benzo(a)pyrene hydroxylation ≥ benzphetamine demethylation ＞ aniline hydroxylation in magnitude. Defluorination of enflurane also markedly decreased in tumor tissues comparing with normal livers. Conclusions: These marked reductions in the compositions and in vitro metabolic activities, including defluorination of anesthetics, in the cytochrome P450-dependent monooxygenases within the tumor tissues characterize the unique pattern of xenobiotic metabolism in patients with hepatocellular carcinoma.

關鍵字

Metabolism: defluorination ； Carcinoma: hepatocellular ； Enzymes: cytochrome P450 monooxygenases

並列摘要

背景：原發性肝細胞癌好發於東方人尤其是中國人之中，該類病人經診斷後，多半會接受手術、化學藥物等治療，而暴露於各種藥物之下，因此瞭解這類病人細胞色素P450酵素系統，代謝外來物質及吸入性麻醉劑的能力，具有臨床的意義，亦為本研究探討的主題。方法：八位原發性肝細胞癌病人，經外科手術切除後之新鮮肝癌及正常部份肝組織，與五位非肝臟疾病病人之肝組織做比較，評估組織中細胞P450含量，以及同型酵素P450 1A1，2B1及2E1之代謝活性，並以Enflurane去氟化活性，來評估其對於吸入性麻醉劑代謝之能力。結果：肝細胞癌組織微粒體蛋白含量明顯下降，細胞色素P450總量及各組成酵素均減少（p＜0.01），癌細胞遠端之正常肝組織酵素含量，雖比對照正常組稍低，但統計上並無差別。酵素活性方面，細胞色素P450 1A1，2B1及2E1活性均下降，以特殊受質代謝反應下降程度而言，依序為1A1≥2B1≥2E1。至於對Enflurane去氟化之活性，肝癌組織亦大幅降低（p＜0.05）。結論：肝細胞癌病人肝內細胞色素P450酵素含量及活性均減少，意謂此類病人對於藥物之活化與去活化能力均下降，因此在接受各種藥物治療時，應考慮其藥物動力學之改變，以及可能影響之藥物交互作用。

並列關鍵字

藥物代謝：去氟化活性 ； 肝細胞癌 ； 酵素：細胞色素P450單氧酵素