Suicidal destruction of cytochrome P-450 and reduction of ferrochelatase activity by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6- trimethylpyridine and its analogues in chick embryo liver cells

GS Marks, DT Allen, CT Johnston, EP Sutherland, K Nakatsu and RA Whitney

The ferrochelatase-reducing activity and cytochrome P-450- and heme- destructive effects of a variety of analogues of 3,5-diethoxycarbonyl- 1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. A group of DDC analogues was found in which an inability to reduce ferrochelatase activity corresponded with an inability to cause cytochrome P-450 and heme destruction. In a second group of DDC analogues, the ability to reduce ferrochelatase activity corresponded with the ability to cause cytochrome P-450 and heme destruction. These observations support the idea that the protoporphyrin IX moiety of N- alkylprotoporphyrin IX originates from the heme moiety of cytochrome P- 450. A third group of DDC analogues caused cytochrome P-450 and heme destruction despite an inability to reduce ferrochelatase activity. With this third group of DDC analogues, the heme moiety of cytochrome P- 450 is likely degraded to products other than N-alkylporphyrins. The inability of several lipophilic DDC analogues [4-benzyl, 4-isopropyl, 4- cyclohexyl, 4-(3-cyclohexenyl)] to reduce hepatic ferrochelatase activity may explain their low porphyrinogenicity. The pattern of porphyrin accumulation produced in response to two DDC analogues that did not inhibit ferrochelatase was investigated using high performance liquid chromatography. Coproporphyrin was the major porphyrin to accumulate in response to the 4-isopropyl analogue and uro- and heptacarboxylic acid porphyrins in response to the 4-benzyl analogue. These patterns of porphyrin accumulation are consistent with the inability of these analogues to inhibit ferrochelatase.

Volume 27, Issue 4, pp. 459-465, 04/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics

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