Journal Article

Increased metabolizing activities of the tricarboxylic acid cycle and decreased drug metabolism in hepatocellular carcinoma

Hiroyuki Fukuda, Masaaki Ebara, Mitsunobu Okuyama, Nobuyuki Sugiura, Masaharu Yoshikawa, Hiromitsu Saisho, Ryo Shimizu, Naomi Motoji, Akiyo Shigematsu and Takaho Watayo

in Carcinogenesis

Volume 23, issue 12, pages 2019-2023
Published in print December 2002 | ISSN: 0143-3334
Published online December 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.12.2019
Increased metabolizing activities of the tricarboxylic acid cycle and decreased drug metabolism in hepatocellular carcinoma

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The aim of this study was to determine the metabolizing activities in the liver of patients with hepatocellular carcinoma (HCC). Thin-layer chromatography autoradioluminography was used to measure metabolizing activities. Succinate-producing activity (SPA) was used as an indicator of metabolizing activity of the tricarboxylic acid (TCA) cycle in mitochondria, and diazepam-N-demethylating activity (DZ-DA), diazepam-3-hydroxylating activity (DZ-HA) and tolbutamide-methyl-hydroxylating activity (TB-HA) as indicators of drug metabolizing activities by P-450. SPA and drug-metabolizing activity of HepG2 cells were examined to compare with those of human liver specimens. Liver biopsy specimens of 30 patients and surgical specimens of eight patients with HCC were studied. SPA of HepG2 cells was as high as that of human tumor tissue, and DZ-DA, DZ-HA and TB-HA were undetectable in HepG2 cells. SPA and DZ-HA of non-tumor tissue in biopsy samples were significantly higher than those in resected liver specimens (P < 0.05). In biopsy specimens, SPA was significantly higher in tumor tissue than in non-tumor tissue (P < 0.05), and DZ-DA, DZ-HA and TB-HA were significantly lower in tumor tissue (P < 0.01). SPA was significantly higher in large tumors (≥30 mm) than in small tumors <30 mm (P < 0.05), and TB-HA was significantly lower in large tumors than in small tumors (P < 0.01). DZ-DA and TB-HA significantly decreased with the progression of the tumor differentiation (P < 0.05). In conclusion, HCC has increased metabolizing activities of the TCA cycle and decreased drug-metabolizing activities.

Keywords: DMA, drug-metabolizing activity; DZ-DA, diazepam-N-demethylating activity; DZ-HA, diazepam-3-hydroxylating activity; G-6-P, glucose-6-phosphate; HCC, hepatocellular carcinoma; SPA, succinateproducing activity; TB-HA, tolbutamide-methyl-hydroxylating activity; TCA, tricarboxylic acid; TLC-ARLG, thin-layer chromatography autoradioluminography.

Journal Article.  3817 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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