Synergistic induction of delta-aminolevulinic acid synthase activity by N-ethylprotoporphyrin IX and 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-isobutylpyridine .
The levels of the cellular free heme pool in chick embryo hepatocyte culture were lowered using N-ethylprotoporphyrin IX (N-ethylPP) and analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), and the effect on delta-aminolevulinic acid synthase (ALAS) was examined. N-EthylPP, which lowers cellular heme levels by inhibiting ferrochelatase activity, produced an induction of ALAS activity to 444% of control at 3 hr after its administration. 4-Ethyl DDC, which lowers heme levels by destroying the heme moiety of cytochrome P-450 and lowering ferrochelatase activity, caused an induction of ALAS to 565% of control at 12 hr after administration. 4-Isobutyl DDC, which lowers heme levels by destroying the heme moiety of cytochrome P-450, induced the activity of ALAS to 289% of control at 3 hr after administration. This indicates that ferrochelatase inhibition is a more important mechanism of heme lowering than alkylation of cytochrome P-450 heme when both heme-depleting mechanisms are acting in chick embryo liver cells. It was anticipated that administration of a combination of 4-isobutyl DDC plus N-ethylPP would mimic the effect of 4-ethyl DDC. However, this combination induced ALAS activity to levels that were much greater than those observed after 4-ethyl DDC (1257% of control at 12 hr). This synergistic induction may be attributable to lowering of free heme levels to the point where transcription, translation, and translocation of ALAS are all derepressed.
Mackie
J E
JE
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Marks
G S
GS
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003997:Dicarbethoxydihydrocollidine / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004357:Drug Synergism; D004790:Enzyme Induction; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004095:Dihydropyridines; D011166:Porphyrins; D011524:Protoporphyrins; D003997:Dicarbethoxydihydrocollidine; C030827:N-ethylprotoporphyrin IX; D000624:5-Aminolevulinate Synthetase