Induction of hepatic cytochromes P450 in dogs exposed to a chronic low dose of polychlorinated biphenyls

Abstract

Induction of cytochrome P450 isoforms, specifically CYP1A1, and their catalytic activities are potential biomarkers of environmental contamination by polychlorinated biphenyls (PCBs). In this study, dogs were exposed to 25 ppm or 5 ppm Aroclor 1248 (PCB mixture) daily in their diet for 10 or 20 weeks, respectively. Relative to controls, hepatic microsomes from dogs dosed with PCBs had higher levels of CYP1A1 detected in immunoblots and higher levels of EROD activity, but low levels of induction for CYP2B and PROD activity. Concentrations of 96 PCB congeners in serum and liver were evaluated using capillary chromatography. Results showed that all dogs exposed to PCB mixtures had higher levels of PCB in serum and liver. Dogs preferentially sequestered highly chlorinated PCB congeners in liver relative to serum. With these experiments, we demonstrated that EROD activity was a potentially sensitive marker of PCB exposure at 5 and 25 ppm. Furthermore, CYP1A1 and EROD activity were maximally induced in dogs consuming dietary concentrations only 2.5 times the maximal permissible level for human food (FDA). The value of CYP1A1 induction as a biomarker of PCB exposure was tenuous because neither CYP1A1 levels nor EROD activity correlated with total PCB body burden. However, a small subset of congeners were identified in liver that may strongly influence EROD and PROD induction. Finally, two dogs in the 25 ppm dose group were fasted for 48 h. After 24 h of fasting, several new congeners appeared in the serum and remained in the serum for the remainder of the fast. The fast caused a 293% increase in PCB concentration in serum. This increase has strong implications regarding mobilization of toxic PCBs in wildlife during fasting (e.g., migration, hibernation).

Comparative hepatic activity of xenobiotic‐metabolizing enzymes and concentrations of organohalogens and their hydroxylated analogues in captive greenland sledge dogs (Canis familiaris)

“…By comparison, in the study by Korytko et al [40], in which a 5-ppm dose of PCB mixture (Aroclor 1248) was administered daily via the diet to adult female mongrel dogs during a 20-week period, liver microsomal EROD activity was roughly threefold higher in the exposed individuals relative to the controls, and this was associated with a fourfold increase in serum ⌺PCB concentrations (from 0.3 to 1.2 ng/g wet wt). By comparison, in the study by Korytko et al [40], in which a 5-ppm dose of PCB mixture (Aroclor 1248) was administered daily via the diet to adult female mongrel dogs during a 20-week period, liver microsomal EROD activity was roughly threefold higher in the exposed individuals relative to the controls, and this was associated with a fourfold increase in serum ⌺PCB concentrations (from 0.3 to 1.2 ng/g wet wt).…”

“…Metabolic degradation of a large number of xenobiotic substrates has been associated with specific dog CYP isoenzymes and their hepatic microsomal activities. In another study, mongrel dogs exposed through the diet to a PCB mixture (Aroclor 1248) had higher liver microsomal CYP1A1 content based on immunoblots and higher EROD activity, whereas no induction of CYP2B-like activity based on pentoxyresorufin-O-deethylase activity was found [40]. For example, dog liver mRNA of CYP1A1/2 and CYP2C21 was first purified from PCB-treated beagle dogs [33].…”

Temporal kinetics and concentration–response relationships for induction of CYP1A, CYP2B, and CYP3A in primary cultures of beagle dog hepatocytes

“…Dog CYP1A1/2, CYP2B11, and CYP3A12 have been shown to be inducible by the prototypical human CYP inducers ␤-naphthoflavone (BNF), phenobarbital (PB), and rifampin (RIF) [8][9][10]. It has been established that species differences in CYP induction exist.…”

From Dogs to Frogs: How Pets, Laboratory Animals, and Wildlife Aided in Elucidating Harmful Effects Arising from a Hazardous Dumpsite

“…Once again, laboratory studies confirmed the likely role of PCBs in decreasing the levels of thyroxine in pet dogs at Akwesasne. After 20 wk of exposure, dogs consuming 5 ppm of Aroclor had a mean level of 4.98 ppb of PCBs in their serum, and those consuming 25 ppm had 9.86 ppb of PCBs in their serum (Korytko et al 1999). Both groups had lower average PCB blood levels than Akwesasne dogs.…”