Induction of cytochrome P450 enzymes in the livers of rats treated with the pyrrolizidine alkaloid retrorsine.
Retrorsine is a member of the pyrrolizidine alkaloid (PA) family of naturally occurring compounds found in a large number of plant species worldwide. The cytotoxic, mutagenic, and antimitotic effects of PAs have made them targets for studies designed to determine their potential contributions to carcinogen esis and their usefulness for anticancer therapy. Evidence from the literature suggests that bioactivation of PAs by liver cytochrome P450 (CYP) enzymes is required for their toxicity. However, the specific CYP isozymes that are involved in retrorsine metabolism have not been identified. To address this issue, we administered retrorsine to a cohort of young adult male rats and examined induction or enhanced expression of mRNA and protein for widely studied hepatic CYP isoforms spanning four families together with the essential enzyme CYP reductase. The protein levels of normally expressed CYPs 1A2, 2B1/2, and 2E1 increase significantly in rat liver microsomes from retrorsine-treated rats compared to untreated control rats (P < 0. 05), but protein levels of CYP 4A3, CYP 3A1, and CYP reductase were unchanged after retrorsine treatment. In addition, CYP 1A1 mRNA and protein, which are not detectable in the livers of control rats, were induced after retrorsine exposure. The results of the present study demonstrate enhanced or induced expression of hepatic CYPs 1A1, 1A2, 2E1, and 2B1/2 in response to retrorsine exposure in rats, suggesting that one or more of these enzymes may be involved in retrorsine metabolism.
Gordon
G J
GJ
Department of Pathology and Laboratory Medicine Curriculum in Toxicology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599, USA.
Coleman
W B
WB
Grisham
J W
JW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004790:Enzyme Induction; D019084:Fluorescent Antibody Technique, Indirect; D007124:Immunoenzyme Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D011763:Pyrrolizidine Alkaloids; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C003300:retrorsine