Depletion of cytochrome P-450 by thyroid hormone and cobalt-protoporphyrin IX in rat liver: evidence that susceptibility varies among forms of the heme protein.
The ability of 3,5,3'-triiodothyronine (T3) and cobalt-protoporphyrin LX (CoPP) to alter the levels of the cytochrome P-450 isoforms, CYP3A2, CYP2E1, CYP2B1 and CYP2B2, was examined in vitro in thyroidectomized adult male rats. With the exception of CYP2B2, CoPP administration resulted in a decline in each of the cytochrome P450 isoforms examined. The effects of T3 administration on immunoreactive levels of cytochrome P-450 were also examined in the liver of thyroidectomized rats. T3 treatment produced a marked depletion in all four cytochrome P-450 isoforms examined. Moreover, this T3-mediated depletion of hepatic cytochrome P-450 occurred in the absence of elevated heme oxygenase levels but in the presence of increased delta-aminolevulinate synthase activity. Thus, CoPP and T3 appear capable of producing isoform-specific downregulation of cytochrome P-450 in the liver of thyroidectomized rats. Based on relative levels of immunoreactive protein, the phenobarbital-inducible isoforms, CYP2B1 and CYP2B2, are most susceptible to T3-mediated suppression. Evidence is presented to suggest that these agents elicit these effects by entirely different mechanisms.
Rosenberg
D W
DW
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs 06268, USA.
Drummond
G S
GS
Smith
T J
TJ
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013965:Thyroidectomy; D014284:Triiodothyronine / Q000494:pharmacology*
D007527:Isoenzymes; D011524:Protoporphyrins; D014284:Triiodothyronine; C007095:cobaltiprotoporphyrin; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital