Inactivation of multiple hepatic cytochrome P-450 isozymes in rats by allylisopropylacetamide: mechanistic implications.
In vivo administration of the porphyrogenic agent allylisopropylacetamide (AIA) to phenobarbital-pretreated rats results in marked loss of hepatic cytochrome P-450 content. Using isozyme-selective functional markers, we now show that such loss reflects inactivation of several phenobarbital-inducible and constitutive isozymes. Some of the isozymes (P-450a,b,h and PB-1) are largely reparable by reconstitution with exogenous hemin, indicating that after AIA-mediated loss of their prosthetic heme, their apoprotein moieties are essentially intact and functionally reconstitutable with hemin. On the other hand, after AIA-mediated inactivation, isozymes such as cytochrome P-450p remain refractory to such repair. The cause for such intractability remains somewhat elusive since AIA-mediated alkylation of the apocytochrome, proteolytic loss of the hemoprotein, or even irreversible binding of prosthetic heme catabolites to the apocytochrome does not appear to be responsible.
Bornheim
L M
LM
Underwood
M C
MC
Caldera
P
P
Rettie
A E
AE
Trager
W F
WF
Wrighton
S A
SA
Correia
M A
MA
D000081:Acetamides / Q000008:administration & dosage*; D000478:Alkylation; D000502:Allylisopropylacetamide / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D004334:Drug Administration Schedule; D006427:Hemin / Q000008:administration & dosage; D007158:Immunologic Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology*; D051381:Rats
D000081:Acetamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D000502:Allylisopropylacetamide; D006427:Hemin