J. Biol. Chem., Vol. 255, Issue 21, 10128-10133, 11, 1980
Structural and functional reconstitution of hepatic cytochrome P-450 in vivo. Reversal of allylisopropylacetamide-mediated destruction of the hemoprotein by exogenous heme
GC Farrell and MA Correia
After the heme moiety of hepatic cytochrome P-450 in rats had been
destroyed by allylisopropylacetamide (AIA), intravenously injected heme
significantly increased the cytochrome P-450 content and mixed function
oxidase activity of liver microsomes. (The term "heme" is used throughout
this paper for iron protorphyrin IX, irrespective of its redox state). In
the absence of AIA treatment, heme administration failed to elicit these
effects. The heme-mediated increase of cytochrome P-450 was most pronounced
in phenobarbital-pretreated rats (46%), but was detectable also in
3-methylcholanthrene-pretreated (6%) and in untreated animals (7%).
Restoration of mixed function oxidase activity by heme appeared to depend
on reconstitution of cytochrome P- 450 and was greatest for oxidases whose
activity is stimulated by phenobarbital. Under optimal experimental
conditions, heme enhanced the residual activity of ethylmorphine
N-demethylase 3-fold when 92% of the initial enzyme activity had been
destroyed by AIA. Reconstitution of cytochrome P-450 was dependent on the
relative amount of cytochrome P- 450 destroyed by AIA and on the dose of
heme administered. Formation of holocytochrome P-450 appeared to be
independent of apoprotein synthesis as it was unaffected by cycloheximide.
Thus, reconstitution of cytochrome P-450 following AIA-mediated destruction
of its original prosthetic heme reflects direct incorporation of
administered heme into residual apoprotein in the endoplasmic reticulum.
These findings demonstrate that exogenous heme can partially restore the
structure and function of hepatic cytochrome P-450 following its
drug-mediated destruction.
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