Comparative xenobiotic metabolism between Tg.AC and p53+/- genetically altered mice and their respective wild types.
The use of transgenic animals, such as v-Ha-ras activated (TG:AC) and p53+/- mice, offers great promise for a rapid and more sensitive assay for chemical carcinogenicity. Some carcinogens are metabolically activated; therefore, it is critical that the altered genome of either of these model systems does not compromise their capability and capacity for metabolism of xenobiotics. The present work tests the generally held assumption that xenobiotic metabolism in the TG:AC and p53+/- mouse is not inherently different from that of the respective wild type, the FVB/N and C57BL/6 mouse, by comparing each genotype's ability to metabolize benzene, ethoxyquin, or methacrylonitrile. Use of these representative substrates offers the opportunity to examine arene oxide formation, aromatic ring opening, hydroxylation, epoxidation, O-deethylation, and a number of conjugation reactions. Mice were treated by gavage with (14)C-labeled parent compound, excreta were collected, and elimination routes and rates, as well as (14)C-derived metabolite profiles in urine, were compared between relevant treatment groups. Results of this study indicated that metabolism of the 3 parent compounds was not appreciably altered between either FVB/N and TG:AC mice or C57BL/6 and p53+/- mice. Further, expression of CYP1A2, CYP2E1, CYP3A, and GST-alpha in liver of naive genetically altered mice was similar to that of corresponding wild-type mice. Thus, these results suggest that the inherent ability of TG:AC and p53+/- mice to metabolize xenobiotics is not compromised by their altered genomes and would not be a factor in data interpretation of toxicity studies using either transgenic mouse line.
Sanders
J M
JM
Laboratory of Pharmacology and Chemistry, National Toxicology Program, National Institute of Environmental Health Sciences, MD C3-02, P.O. Box 12233, Research Triangle Park, North Carolina 27709-2233, USA. sandersm@niehs.nih.gov
Burka
L T
LT
Chanas
B
B
Matthews
H B
HB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001323:Autoantibodies / Q000187:drug effects*; D001554:Benzene / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D002244:Carbon / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005015:Ethoxyquin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine*; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006579:Heterozygote; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008689:Methacrylates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011868:Radioisotopes; D015262:Xenobiotics / Q000378:metabolism* / Q000633:toxicity
D001323:Autoantibodies; D007527:Isoenzymes; D008689:Methacrylates; D009570:Nitriles; D011868:Radioisotopes; D015262:Xenobiotics; C094307:anti-liver cytosolic protein 1; C008385:methacrylonitrile; D002244:Carbon; D003577:Cytochrome P-450 Enzyme System; D005015:Ethoxyquin; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D001554:Benzene