Synergism of aromatic amines and benzo[a]pyrene in induction of Ah receptor-dependent genes

Abstract

Aromatic amines have been shown to cause bladder cancer. However, epithelial cells of the urinary bladder, cells of origin of bladder cancer, may be exposed to numerous substances besides aromatic amines. In the present study, we analysed possible interactions between the aromatic amines 4-aminobiphenyl (4-ABP) as well as 2-naphthylamine (2-NA) and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). For this purpose we incubated primary porcine urinary bladder epithelial cells (PUBEC) with concentrations of 1 to 50 M 4-ABP with and without coexposure to B[a]P. As expected B[a]P increased mRNA expression of cytochrome P450 1A1 (CYP1A1), whereas 4-ABP had no eVect. However, when co-exposed 4-ABP enhanced the induction of CYP1A1 by B[a]P. This result was conWrmed by Western blot analysis of CYP1A1 protein expression. A similar eVect as for CYP1A1 was also observed for cyclooxygenase-2 (COX-2) and UDP-glucuronosyltransferase 1 (UGT1). Next, we studied co-exposures of 2-NA and B[a]P. Similar as for 4-ABP also 2-NA enhanced B[a]P-mediated induction of CYP1A1. Our results demonstrate that some aromatic amines may enhance the inXuence of B[a]P on Ah receptor-dependent genes.

Synergistic and antagonistic interactions of binary mixtures of polycyclic aromatic hydrocarbons in the upregulation of CYP1 activity and mRNA levels in precision-cut rat liver slices

“…It has already been reported that benzo[ g,h ,i]perylene increased the B[a]P‐mediated CYP1A1 transcription in HepG2 cells as well as B[a]P DNA adducts (Cherng et al, ). Similarly, some aromatic amines were shown to interact synergistically with B(a)P in the transcription of Ah receptor‐dependent genes (Borza et al, ). It is worthwhile to point out that 1‐MP, which failed to interact with B(a)P, is not a ligand for this receptor, whereas B(b)F, the only compound that antagonized B(a)P in the present study, is also the only PAH that has higher affinity than B(a)P for this receptor (Pushparajah et al, ).…”

Activation of the aryl hydrocarbon receptor by carcinogenic aromatic amines and modulatory effects of their N-acetylated metabolites

“…genes through the activation of AhR (Borza et al 2008;Dumont et al 2010). 2-NA and 4-ABP have been shown to induce CYP1A1 in PUBEC cells (Borza et al 2008).…”

“…Certain aromatic amides (N-acetyl-AA) such as 2-acetylaminofluorene (2-AAF) and 2-acetylaminophenanthrene (2-AAP) have been reported to bind to the rat AhR (Cikryt et al 1990). Interestingly, a higher induction of CYP1A genes was observed (Borza et al 2008) when porcine urinary bladder epithelial cells (PUBEC) were co-exposed to B(a)P in combination with 4-ABP or 2-NA (as compared to B(a)P). However, these AAs did not induce the expression of CYP1A in the absence of B(a)P. In addition, some AhR target genes, including CYP1A1 and CYP1A2, are strongly regulated in response to acute and chronic exposure to heterocyclic aromatic amines (HAA) (Dumont et al 2010).…”

Causation of human urothelial cancer: there are challenging new data!

“…Having this in mind, Borza et al (2008) studied the interaction between the aromatic amine 4-aminobiphenyl (1-50 µM) and benzo[a]pyrene (1 µM) in the PUBEC model. As expected, benzo[a]pyrene increased mrNA expression of CYP1A1, whereas 4-aminobiphenyl alone had no such effect.…”