2,2-Dialkyl-1,2-dihydroquinolines: cytochrome P-450 catalyzed N-alkylporphyrin formation, ferrochelatase inhibition, and induction of 5-aminolevulinic acid synthase activity.
Incubation of 2,4-diethyl-1,2-dihydro-2-methylquinoline (DMDQ) with hepatic microsomes from rats pretreated with phenobarbital, 3-methylcholanthrene, pregnenolone-16 alpha-carbonitrile, or dexamethasone results in minor loss of the cytochrome P-450 chromophore and accumulation of a hepatic pigment. The hepatic pigment consists of the four regioisomers of N-ethylprotoporphyrin IX and minor amounts of the corresponding N-methyl regioisomers. Exposure of chick embryo liver cells to DMDQ results in inhibition of their ferrochelatase activity, induction of their 5-aminolevulinic acid synthase activity, and accumulation of protoporphyrin IX. 1,2-Dihydro-2,2,4-trimethylquinoline (TMDQ) causes negligible loss of cytochrome P-450 in rat liver microsomes but in vivo still produces the four N-methylprotoporphyrin IX regioisomers in low yield. Furthermore, it inhibits ferrochelatase activity, elevates 5-aminolevulinic acid synthase activity, and causes protoporphyrin IX accumulation in cultured chick embryo hepatocytes. One-electron oxidation of the 2,2-dialkyl-1,2-dihydroquinolines to radical cations is postulated to result in N-alkylation of the prosthetic heme group of cytochrome P-450. The N-alkylprotoporphyrins IX thus formed are potent inhibitors of ferrochelatase. Inhibition of ferrochelatase causes the induction of 5-aminolevulinic acid synthase and the accumulation of protoporphyrin IX. Heme alkylation and ferrochelatase inhibition may be generally associated with substrates that are subject to cytochrome P-450 mediated oxidative extrusion of alkyl radicals.
Lukton
D
D
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143.
Mackie
J E
JE
Lee
J S
JS
Marks
G S
GS
Ortiz de Montellano
P R
PR
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000378:metabolism*; D011166:Porphyrins / Q000378:metabolism; D011798:Quinaldines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
D011166:Porphyrins; D011798:Quinaldines; C072641:2,4-diethyl-1,2-dihydro-2-methylquinoline; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase; D005294:Ferrochelatase