Acute effect of amitriptyline, phenobarbital or cobaltous chloride on delta-aminolevulinic acid synthetase, heme oxygenase and microsomal heme content and drug metabolism in rat liver.
Cobaltous chloride (CoCl2) caused very marked decreases of cytochrome P-450, b5 and total heme contents and an increase of heme oxygenase activity. On the contrary, phenobarbital (PB) increased hepatic drug-metabolizing enzymes, but the total heme content remained unchanged. On the other hand, amitriptyline (AMT) caused a marked increase of delta-aminolevulinic acid (delta-ALA) synthetase activity at 12 and 24 hr. In addition, the contents of total heme and cytochrome b5 and the activities of aminopyrine (AM) N-demethylase and aniline (AN) hydroxylase at 24 hr were also increased by AMT, whereas cytochrome P-450 content did not change. This may be explained by the fact that AMT would increase hepatic heme synthesis through the prolonged induction of delta-ALA synthetase, but it may not cause an increase in cytochrome P-450 heme because there are increases in the contents of cytochrome b5 and total heme.
Hoshi
K
K
Department of Pharmacology, Hokkaido Institute of Pharmaceutical Sciences, Otaru, Japan.
Senda
N
N
Fujino
S
S
D000624:5-Aminolevulinate Synthetase / Q000037:antagonists & inhibitors*; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D003035:Cobalt / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D003573:Cytochrome b Group; D004364:Pharmaceutical Preparations; D000639:Amitriptyline; D003035:Cobalt; D006418:Heme; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; C018021:cobaltous chloride; D010634:Phenobarbital