Induction of CYP1A and glutathione S-transferase activities by 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatocyte cultures

• Published in: Carcinogenesis (New York) 1995-04, Vol.16 (4), p.943-946
• Main Authors: Schrenk, D., Stilven, T., Gohl, G., Viebahn, R., Bock, K.W.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cells, Cultured; Chemical and industrial products toxicology. Toxic occupational diseases; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - genetics; DNA Probes; Enzyme Induction - drug effects; Female; Gene Expression; Glutathione Transferase - biosynthesis; Glutathione Transferase - drug effects; Glutathione Transferase - genetics; Humans; Liver - drug effects; Liver - enzymology; Liver - surgery; Male; Medical sciences; Middle Aged; Oxidoreductases - biosynthesis; Oxidoreductases - drug effects; Oxidoreductases - genetics; Polychlorinated Dibenzodioxins - pharmacology; RNA - genetics; RNA - isolation & purification; Toxicology; Various organic compounds
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/16.4.943

Induction of CYP1A and glutathione S-transferase activities with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in human hepatocytes in primary culture to investigate the variability of inducibility and the potency of TCDD. Determining induction of 7-ethoxyresorufin O-deethylase activity, preferentially catalyzed by CYP1A isozymes, we obtained concentration—response diagrams in TCDD-treated hepatocyte cultures from transplant donors and patients undergoing hepatic surgery. At a concentration of 10−10 M TCDD approximately half-maximal induction of CYP1A was observed. Northern analysis of CYP1A gene expression showed a similar concentration — response relationship. In comparison with rat hepatocytes, human hepatocytes were about 10-fold less sensitive towards the CYP1A-inducing effect of TCDD. No pronounced interindividual differences in the inducing potency of TCDD (concentration which leads to half-maximal induction) were obvious in the six human individuals studied, whereas the efficacy of CYP1A induction was highly variable. In addition, inducibility of glutathione S-transferase (GST) activity also revealed a considerable degree of interindividual variation, i.e. a complete lack of induction in three out of six hepatocyte preparations and a highly variable efficacy of GST induction among responders which was not related to CYP1A inducibility.