Differential induction of CYP1A1 in duodenum, liver and kidney of rats after oral intake of soil containing polycyclic aromatic hydrocarbons

Abstract

We have analyzed the induction of the cytochrome P450 enzyme CYP1A1 as a biomarker of effect in duodenum, liver and kidney of rats after oral intake of contaminated soil particles. The soil samples originated from industrial sites and were contaminated with polycyclic aromatic hydrocarbons (PAH) to variable extents, ranging from 60 to 4700 mg PAH/kg soil. Soil samples were administered for one week as a mixture with commercial rodent diets. After exposure, microsomes of several organs were prepared and analyzed for CYP1A1, enzymatically and by Western blots. All contaminated soils led to induction of CYP1A1 in duodenal mucosa cells, regardless of their extent of contamination, showing that relevant doses were mobilized in the gastrointestinal tract and adsorbed. Subsequent distribution of non-metabolized compounds is indicated by induction of CYP1A1 in the liver. However, some samples did not lead to a response in the liver, due to their quantitative and qualitative contaminant composition. In accordance with previous results, there is a sigmoidal dose-response relationship between induction of hepatic CYP1A1 levels and the soil contamination with higher condensates of PAH. In contrast, the response in the duodenum appeared to be hyperbolic and correlated well with the amounts of total PAH. Highly contaminated soil, being nearly devoid of higher condensates of PAH, led to pronounced induction in the duodenum but failed to induce CYP1A1 in the liver. Successful passage of contaminants through the intestinal barrier and the liver compartment is shown by increased CYP1A1 expression in the kidney. Compared with enzyme levels induced in the liver, those of the kidney are much lower and amount to only about 1/20 of the liver values for soils with high induction potential. Hence, oral PAH intake leads to differential induction patterns of CYP1A1 in duodenum, liver and kidney of rats. The observations raise questions concerning the role of the primary duodenal PAH metabolism in preventing contaminant-dependent hazardous effects, and of the significance of differential CYP1A1 expressions for carcinogenic processes in several tissues.

Induction of cytochrome P450 1A1 in multiple organs of minipigs after oral exposure to soils contaminated with polycyclic aromatic hydrocarbons (PAH)

“…This EROD activity may be attributed to P450 enzymes other than CYP1A1, such as constitutively expressed CYP1A2 (Sesardic et al 1990). In accordance with this observation, background EROD activities of rat and human liver microsomes are in the same range (Table 3) (Roos et al 1996, Roos 2000, 2002. Thus, CYP1A1 is not expressed in liver, duodenum and kidney of nonexposed minipigs and rats.…”

“…In contrast, duodenal EROD activities of rats achieved with even higher contaminant doses, i.e. 2,900 versus 530 lg 5-, 6-ring PAH/kg body weight per day for rats and minipigs, respectively, amount to 350 pmol resorufin/mg protein per min only (Roos 2002). Thus, in minipigs, CYP1A1 appears to be more inducible in the duodenum and less inducible in the liver compared to rats.…”

Identification of Human Liver Cytochrome P450 Isoforms Involved in Autoinduced Metabolism of the Antiangiogenic Agent (Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic Acid (TSU-68)

“…5, treatment with TSU-68 caused an apparent increase in the level of CYP1A2 protein in hepatocytes from all three donors. Although CYP1A1 protein was not detected in vehicle-treated hepatocytes as previously reported (Pelkonen et al, 1998;Roos, 2002), TSU-68 treatment increased CYP1A1 protein to detectable levels. TSU-68-treated hepatocytes from donors HH59 and HH393 indicated that the protein levels of CYP1A1 were lower than those of CYP1A2, whereas those from donor HH426 indicated that the protein levels of CYP1A1 were similar to those of CYP1A2.…”

“…In human liver microsomes and untreated hepatocytes, CYP1A protein expression detected by immunoblot analysis is almost entirely due to CYP1A2, with CYP1A1 being rarely detected (Murray et al, 1993;Pelkonen et al, 1998;Roos, 2002). Treatment of hepatocytes with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene preferably induced CYP1A2, but not CYP1A1, proteins, whereas treatment with ␤-naphthoflavone induced CYP1A1 and CYP1A2 proteins at comparable levels (Runge et al, 2000;Xu et al, 2000;Zhang et al, 2006).…”

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

“…Quantitation was achieved with CCD camera digitalised pictures of the stained immunoblots utilising the image analysis software WinCam 2.1 (Cybertech, Berlin, Germany). As reference standard for CYP1A1 detection, liver microsomes from 3-methylcholanthrene treated rats (Roos 2002) were utilised.…”