Induction of CYP1A and glutathione S-transferase activities by 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatocyte cultures.
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.
Schrenk
D
D
Institute of Toxicology, University of Tübingen, Germany.
Stüven
T
T
Gohl
G
G
Viebahn
R
R
Bock
K W
KW
D000328:Adult; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D015342:DNA Probes; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification
D015342:DNA Probes; D000072317:Polychlorinated Dibenzodioxins; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase