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

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Abstract
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.

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