Different mechanisms of handling ingested polycyclic aromatic hydrocarbons in mammalian species: organ-specific response patterns of CYP1A1-induction after oral intake of PAH-contaminated soils

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.

Multi-parametric analysis of cytochrome P450 expression in rat liver microsomes by LA-ICP-MS

“…1 The profiles of CYP enzymes are variable and show clear organ specificities with respect to composition and enzyme levels. 2,3 Furthermore, the adaptive responsivity of the system on exposure to xenobiotics is an important feature meaning that compounds may initiate their own metabolism by induction of a respective CYP enzyme. Shortly after the discovery of the cytochrome P450 in 1958 by Klingenberg 4 and colleagues it became obvious that it is not a single protein but a family of proteins, an aspect nicely summarised in a historical review by Estabrook.…”

Ambient temperature‐mediated changes in hepatic gene expression of a mammalian herbivore (Neotoma lepida)

“…Although animals on the creosote diet treatment were ingesting unequal amounts of creosote resin, which could impact detoxification mechanisms (e.g., Ioannides, ; Roos, Tschirbs, Hack, Welge, & Wilhelm, ; Skopec et al., ), patterns in differential gene expression were apparent (Figure b, comparison C). Animals at the thermoneutral temperature ingested 50% more creosote resin than woodrats at the cooler temperature, yet more transcripts were differentially expressed at 22°C compared to 27°C, including a high number of detoxification‐specific transcripts (Table ).…”

Influence of Exposure Pathways on Tissue Distribution and Health Impact of Polycyclic Aromatic Hydrocarbon Derivatives

“…More importantly, PAHs may have different metabolic pathways in different species, which can lead to different tissue distribution patterns. For example, the minipigs can intercept PAHs, and the rat’s liver could efficiently metabolize PAHs . There was research reported that the proportion of parent PAHs in animal samples was higher than that in the sediments where the samples were collected, while the proportion of methylated derivatives became lower, suggesting that the preferential metabolism of methylated PAHs or the preferential absorption of parent PAHs .…”