Differential effects of partial hepatectomy on hepatic and renal heme and cytochrome P450 metabolism.
Partial hepatectomy has been suggested to affect hepatic and renal cytochrome P450 content and the related drug metabolizing enzyme system. In addition, cytochrome P450 and its dependent activities have been shown to be regulated by the availability of cellular heme. We, therefore, studied cytochrome P450 in addition to the level of heme oxygenase, the rate-limiting enzyme of heme catabolism, and delta-aminolevulinic acid (ALA) synthase, the rate-limiting enzyme of heme synthesis, in the remnant liver and intact kidneys of rats after two-thirds hepatectomy. The level of hepatic heme oxygenase was elevated threefold in partially hepatectomized rats as compared to sham-operated rats, while ALA synthase was decreased by 40%. This was reflected in decreased hepatic cytochrome P450 content, ie, from 0.689 +/- 0.175 nmole/mg to 0.505 +/- 0.089 nmole/mg protein and associated decreased drug metabolizing enzymes: aryl hydrocarbon hydroxylase, 7-ethoxycoumarin-O-deethylase, and benzphetamine N-demethylase, by 40%, 40%, and 47%, respectively. In contrast, renal heme oxygenase was not changed after hepatectomy, whereas renal ALA synthase was increased by fourfold. Renal cytochrome P450, aryl hydrocarbon hydroxylase, 7-ethoxycoumarin-O-deethylase, and benzphetamine N-demethylase were increased after partial hepatectomy by 84%, 360%, 165% and 406%, respectively. These data indicate that partial hepatectomy decreases liver cytochrome P450 levels by inducing heme oxygenase and inhibiting ALA synthase activities. In this situation the kidney plays a substitutive role in metabolizing endogenous substrates oxygenated by cytochrome P450 isozymes.
Solangi
K
K
Department of Pharmacology, New York Medical College, Valhalla 10595.
Sacerdoti
D
D
Goodman
A I
AI
Schwartzman
M L
ML
Abraham
N G
NG
Levere
R D
RD
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006498:Hepatectomy; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats
D007527:Isoenzymes; D006418:Heme; D003577:Cytochrome P-450 Enzyme System