We have previously shown that the p38 MAPK inhibitor SB203580 (SB) significantly induced Cyp1a1 gene expression at the mRNA and activity levels, whereas it dramatically inhibited the induction of Cyp1a1 by TCDD in murine hepatoma Hepa 1c1c7 cells.
In human hepatocellular carcinoma cells (HepG2) with aryl hydrocarbon receptor (AhR) or specificity protein 1 (Sp1) knockdown, we confirmed that AhR and Sp1 are involved in basal CYP1A1 expression.
Clinically relevant concentrations (0.25-5 microM) of As2O3 were demonstrated to inhibit CYP1A activity in primary human hepatocytes and hepatoma Hep3B and HepG2 cells coexposed to 3-methylcholanthrene (3MC), benzo(a)pyrene, or dioxin and the metalloid for 24 h. Inhibition reached 50 and 90% in Hep3B cells treated with 1 and 5 microM As2O3, respectively, and was not due to direct interaction of the metalloid with CYP1A1.
In human cells, such as HepG2 (human hepatocarcinoma), MCF-7 (human breast adenocarcinoma cell line), and HL-60 (human promyelocytic cell line), the expression of CYP1A1 mRNA was also induced by EA4 treatment.
In this study, three representative DL-PCBs, i.e., PCB 77, PCB 126, and 3,4,4',5-tetrachlorobiphenyl (PCB 81), were investigated on their genotoxicity in Chinese hamster V79-derived cell lines genetically engineered for the expression of human CYP1A1, 1A2 and 1B1, and in the human hepatoma C3A cell line, which endogenously expresses various CYPs.
We found that the risk of HCC was elevated in women harboring either heterozygous or homozygous variants of the CYP1A1 gene and the respective OR (and 95% confidence interval) were 6.61 (1.35, 32.43) and 12.00 (1.73, 83.46).