The comparative effects of diethyldithiocarbamate–copper complex with established proteasome inhibitors on expression levels of CYP1A2/3A4 and their master regulators, aryl hydrocarbon and pregnane X receptor in primary cultures of human hepatocytes

Abstract

In the recent years, a therapeutic potential of disulfiram (Antabuse) complex with copper, as an anticancer drug, was recognized towards several cancer cell lines. The proteasome was suggested as one of the cellular targets for this compound. As the therapeutic use of diethyldithiocarbamate-copper complex (CuET) is expected to increase, it is of great interest to know whether this compound may be the source of drug-drug interactions via the induction of biotransformation enzymes, especially cytochromes P450 (CYPs). To this purpose, we examined the effect of CuET and compared it with typical inducers (rifampicin and dioxin) of CYPs and with well-established proteasome inhibitors (MG132 and bortezomib). Diethyldithiocarbamate-copper complex revealed inconsistent and rather modulatory effect on the expression of CYP1A2 and CYP3A4 in several cultures of human hepatocytes. Moreover, it was able to cause neither ubiquitin accumulation nor significant and dose-dependent inhibition of proteasome activity. It had no effect on essential transcription factors involved in regulation of selected CYPs, aryl hydrocarbon (AhR) nor pregnane X receptor (PXR). However, the AhR protein was increased in majority of examined hepatocyte cultures. The main finding of this study is that: (i) disulfiram-copper complex is not the cause of drug-drug interactions via CYP1A2/3A4 induction; (ii) proteasome inhibitors may have different impact on studied parameters in given in vitro system.

2,3,4′,5-tetrahydroxystilbene-2-O-β-D-glucoside exacerbates acetaminophen-induced hepatotoxicity by inducing hepatic expression of CYP2E1, CYP3A4 and CYP1A2

“…AHR and PXR are reported to regulate the expression of CYP1A2 and CYP3A4 38 . Next, whether TSG will induce the nuclear translocation of AHR or PXR in hepatocytes was observed.…”

“…AHR and PXR are found to be responsible for regulating the transcriptional expression of CYP1A2 and CYP3A4 38 , 50 . In this study, TSG promoted the nuclear translocation of AHR and PXR both in vivo and in vitro , which may contribute to the increased expression of CYP1A2 and CYP3A4 induced by TSG.…”

Gene Expression Profiling of 1α,25(OH)2D3 Treatment in 2D/3D Human Hepatocyte Models Reveals CYP3A4 Induction but Minor Changes in Other Xenobiotic‐Metabolizing Genes

“…PHH donor characteristics are as follows: LH28 (male, 48 years), LH29 (male, 74 years) [28,29] , LH47 (male, 47 years), LH49 (male, 38 years), and LH50 (female, 55 years). [30] Hepatocytes were isolated as previously described. [31] Following isolation, PHHs were plated on collagen-coated culture dishes at a density of 1.4 × 10 5 cells cm -2 (BD Biosciences, Le Pont de Claix, France).…”