ABSTRACT
Potential effects of xenobiotics on humans are largely derived from studies with animal models. However, due to species-specific processing of xenobiotics, susceptibilities to xenobiotic-dependent adverse effects are known to differ between species. We analysed the basal expression of cytochrome P450 (CYP) enzymes in several organs of minipigs and rats, and their inducibility upon oral intake of soils containing polycyclic aromatic hydrocarbons (PAH). CYP-specific enzymatic activities were determined in duodenum, liver and kidney microsomes. Upon ingestion of PAH-contaminated soils, CYP1A1 is differentially induced in a tissue-specific and dose-dependent manner in duodenum, liver and kidney of minipigs and rats. In the duodenum, the induction response is low in rats (about 4-fold) but it is high in minipigs (8-230-fold). By contrast, induced hepatic CYP1A1-dependent EROD-activity is higher in rats than in minipigs. The dose-response profile for renal CYP1A1 parallels that in the liver of either species but EROD-activities are 10-20 times lower than in the liver. Liver microsomal CYP2E1 is only slightly modulated in its expression by ingestion of PAH-contaminated soils in both species, whereas CYP3A-dependent testosterone 2beta- and 6beta-hydroxylation is increased in liver of rats but not in minipigs. The hepatic capacity for catechol oestrogen formation, i.e., the 2-hydroxylation of 17beta-oestradiol, is markedly increased in rats but not in minipigs by ingested PAH. It is concluded that different metabolic and transport pathways are used by minipigs and rats to process ingested PAH. Whereas in minipigs the duodenum appears as the first efficient barrier, rats respond by efficient metabolism in the liver. What is not known is which response profile is operative in man.
