Hyper- and hypo-induction of cytochrome P450 activities with Aroclor 1254 and 3-methylcholanthrene in Cyp1a2(-/-) mice.
The response of hepatic mono-oxygenase activities to Aroclor 1254 or 3-methylcholanthrene was investigated in wild-type and Cyp1a2(-/-) mice. Cytochrome P450 concentrations were similar in naïve Cyp1a2(-/-) and wild-type mice. There was no difference between naïve wild-type and Cyp1a2(-/-) animals in 7-ethoxyresorufin and 7-ethoxy-4-trifluoromethylcoumarin dealkylase activities, nor was the induction response after 3-methylcholanthrene any different between the two genotypes. However, both activities were induced to a higher extent in Cyp1a2(-/-) mice after Aroclor 1254. In contrast, 7-pentoxyresorufin dealkylation activity was lower in Cyp1a2(-/-) mice and this differential was maintained during induction by both agents. 7-Methoxy- and 7-benzoxyresorufin dealkylation activities were also lower than wild-type in naïve Cyp1a2(-/-) animals and during 3-methylcholanthrene induction, but showed accelerated induction in Cyp1a2(-/-) mice with Aroclor 1254. Bufuralol 1'- and testosterone 6beta-hydroxylation activities, and P450 characteristics were evaluated 48h after inducer administration. Bufuralol 1'-hydroxylation, a sexual dimorphic activity (female>male) showed no genotype differences in naïve animals. Activity changes varied across gender and genotype, with 3-methylcholanthrene and Aroclor 1254 inducing in male Cyp1a2(-/-), and Aroclor 1254 inducing in female wild-type. Testosterone 6beta-hydroxylation activity was 16% higher in Cyp1a2(-/-) mice and neither 3-methylcholanthrene nor Aroclor 1254 elicited induction. After Aroclor 1254, a 24% increase in P450 concentration with a hypsochromic shift in the ferrous-CO maximum characteristic of CYP1A enzymes occurred in wild-type, compared to no change in either parameter in Cyp1a2(-/-) mice. Induction changes with 3-methylcholanthrene were greater in wild-type mice, a 60% increase in concentration and approximately 2 nm hypsochromic shift versus a 10% increase and approximately 1nm hypsochromic shift in Cyp1a2(-/-) mice. The study demonstrates that deletion of a single P450 can profoundly affect the induction response, as monitored with activities of other P450s, in a manner unrelated to the contribution of the deleted P450 to the activity.
Barker
Melissa L
ML
University of Utah, Department of Pharmacology and Toxicology, Salt Lake City, UT 84112, United States.
Hathaway
Laura B
LB
Arch
Dorinda D
DD
Westbroek
Mark L
ML
Kushner
James P
JP
Phillips
John D
JD
Franklin
Michael R
MR
D000818:Animals; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011078:Polychlorinated Biphenyls / Q000032:analysis
D020111:Chlorodiphenyl (54% Chlorine); D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D019388:Cytochrome P-450 CYP1A2