Liver Haem as a Target for Drug Toxicity

Inactivation of cytochrome P‐450 and production of N‐alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines

“…The green pigments isolated after treatment with the 4-ethyl and 4-propyl dihydropyridines were identified as N-ethyl and N-propyl protoporphyrin, respectively [30], confirming previous conclusions [5,6] that the whole 4-alkyl substituent of a dihydropyridine is transferred to the pyrrole nitrogen. Table 2 Effect of pretreatment of rats with phenobarbitone in vivo and of adding exogenous haematin in vitro on the formation of N-alkylated porphyrins caused in isolated hepatocytes by either AIA or the 4-ethyl dihydropyridine in presence or absence of exogenous haematin.…”

“…The following findings strongly suggest that the endogenous precursor pool is cytochrome P-450: (1) a correlation was found between loss of the cytochrome and production of N-alkylated porphyrins, when the effects of DDC, its 4-ethyl and cl-propyl analogues were compared; (2) the yield of N-alkylated porphyrins could be increased by phenobarbitone, an inducer of cytochrome P-450, whereas the inhibitor SKF 525-A has been shown to decrease the production of N-methyl protoporphyrin after DDC [32]; and (3) finally, when DDC was given to mice at different times after labelling their liver haem with [5-t%]aminolaevulinate, the specific radioactivity of the isolated N-methyl protoporphyrin declined with an apparent half-life of approx. 7 h [30], the t% value given in [33] for the rapidly turning-over component of cytochrome P-450.…”

“…The production of both types of pigments was significantly increased by exogenous haem, particularly after the first 2 h of incubation, by which time production of green pigments from endogenous haem was virtually complete (table 2). More direct evidence for conversion of exogenous haem into green pigment of both classes was obtained by using [t'%]haematin and demonstrating that the pigments, purified by TLC as the free carboxylic acid [9], were radioactive [30].…”

Structural Isomerism and chirality of N‐monosubstituted protoporphyrins

“…It must be emphasized that this concept is still hypothetical: more direct evidence is required that the 2 propionic acid sidechains are in fact involved in the binding of the inhibitory porphyrin to the enzyme. Similar steric factors may be responsible for the less marked inhibition of ferrochelatase observed when the N-substituent is increased in size from 1-2 or more carbon units [17]. This interpretation is supported by the observation that in both the non-inhibitory N-hydroxyethyl protoporphyrin produced by treatment with ethylene [6] and in the weakly inhibitory N-methyl protoporphyrin [18], the loss of inhibitory activity may be largely correlated with the presence of the N-alkyl group on propionic acid-substituted rings [ 19,20].…”

Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible

“…It has been proposed that N-Vol. 226 methylprotoporphyrin may act as a tight-binding inhibitor (De Matteis et al, 1982a;Dailey & Fleming, 1983) capable of interacting with the active site of ferrochelatase with great affinity, but unable to accept the second substrate of the enzyme, a bivalent metal ion, for normal (i.e. tetraco-ordinate) incorporation into the pyrrolic macrocycle (De Matteis et al, 1982a).…”