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Metabolism of hepatic haem and 'green pigments' in rats given 2-allyl-2-isopropylacetamide and ferric citrate. A new model for hepatic haem turnover.

ABSTRACT: We have studied effects of single doses of 2-allyl-2-isopropylacetamide and ferric citrate on hepatic haem turnover in rats. Haem was pre-labelled by intraperitoneal administration of 5-amino-[4-(14)C]laevulinate 4h before other treatments. Computer-assisted analysis of the haem decay curve showed that at least two exponential components were involved implying two haem pools. In control rats the size of the rapidly-turning-over pool was 38% of the total. Treatment with 2-allyl-2-isopropylacetamide alone resulted in a 2.3-fold increase in the fractional size of this pool. Treatment with ferric citrate alone increased the size of this pool 1.8-fold; treatment with both agents together had no measurable effect beyond that produced by 2-allyl-2-isopropylacetamide. The apparent rate constant for disappearance of labelled haem from the first pool was not affected by treatment with 2-allyl-2-isopropylacetamide or ferric citrate, indicating that these treatments affect hepatic haem turnover primarily by altering the distribution of haem synthesized in the liver. The increased haem degradation after treatment with 2-allyl-2-isopropylacetamide alone was associated with the accumulation of ;green pigments' in the liver. These pigments were detectable 1.5h after drug treatment; their total amount increased steadily for 28h and then declined. Despite this increase in amount, radioactivity of the ;green pigment' fraction fell rapidly in a biphasic fashion. Some of the radioactivity that initially was found in the ;green pigment' fraction was later found in an aqueous fraction, not extractable by acidic ethyl acetate. Rats given ferric citrate together with 2-allyl-2-isopropylacetamide accumulated less ;green pigments'.

SUBMITTER: Bonkowsky HL

PROVIDER: S-EPMC1161870 | biostudies-other | 1980 May

REPOSITORIES: biostudies-other

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Project description:1. Factors affecting the norethindrone-mediated conversion of hepatic haem into green pigments have been studied in the rat. Concentrations of haem and green pigments were estimated spectrophotometrically after esterification and separation by silica gel high-pressure liquid chromatography (h.p.l.c.). 2. Accumulation of green pigments in the liver was dependent on the dose of steroid and the time after dosing, maximum values being reached after 4-8h. Phenobarbitone pretreatment of rats resulted in an 8-fold increase in the concentration of green pigments at these times. 3. In microsomal systems in vitro, the formation of green pigments in the presence of NADPH and norethindrone was also dependent on the concentration of steroid and incubation times. Reaction rates very rapidly became non-linear with time, consistent with the self-catalysed destruction of the form(s) of cytochrome P-450 responsible for the metabolic activation of norethindrone. Microsomal mixtures incubated for a short period of time (1min) with norethindrone gave only one green-pigment peak after h.p.l.c. Longer incubation times gave four or five additional green pigments. Results suggested that multiple green pigments may arise by metabolic transformation of a single precursor. 4. When liver haem was prelabelled with (14)C by using 5-amino[4-(14)C]laevulinic acid, subsequent dosing with norethindrone in vivo gave rise to three major (14)C-labelled-green-pigment peaks on h.p.l.c. None of these components had the same retention times as the green pigments produced by microsomal fractions in vitro. 5. When liver haem was prelabelled with (59)Fe by using (59)FeCl(3), norethindrone administration resulted in the detection of (59)Fe-labelled green pigments if subsequent esterification was carried out under neutral conditions with trimethyloxonium tetrafluoroborate, but not when carried out under acidic conditions with methanol/H(2)SO(4). These results suggested that green pigments normally contain chelated iron and that metal-free green pigments are not produced by the liver.

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Metabolism of hepatic haem and 'green pigments' in rats given 2-allyl-2-isopropylacetamide and ferric citrate. A new model for hepatic haem turnover.

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