PubMed · 320127
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J Svanvik, O Lundgren. 1977. Gastrointestinal circulation.. https://pubmed.ncbi.nlm.nih.gov/320127/
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In erythropoietic protoporphyria, accumulation of protoporphyrin has been found in various tissues and liver cirrhosis occurs frequently in this disease, probably due to toxic dark effects of protoporphyrin. We have studied the effect of porphyrins on various enzymic functions in rat liver microsomes. Incubation of microsomes with protoporphyrin resulted in a concentration-dependent inhibition of the oxidation of 7-ethoxycoumarin and aminopyrine by the cytochrome P-450 system. Kinetic analysis showed a decrease in Vmax., whereas the Km was not affected (non-competitive inhibition). Furthermore, reduction of cytochrome c by the NADPH-cytochrome P-450 reductase and by the NADH-cytochrome b5 reductase was inhibited. However, the activity of the reductases was only affected when the microsomes were pre-incubated with protoporphyrin, and it was found that the inhibition was dependent on the duration of the pre-incubation. Kinetic analysis again revealed non-competitive inhibition. When these experiments were repeated with uroporphyrin, no inhibition could be observed. With Stern-Volmer plots it was demonstrated that this was most likely caused by the localization of the porphyrins: protoporphyrin is localized in the membrane, whereas uroporphyrin remains in solution. From these results it is concluded that accumulation of protoporphyrin in the liver may markedly affect the cytochrome P-450 system and thus its detoxification function.
The aminopyrine breath test (ABT) was performed during hepatic autotransplantation in the pig. The test is reproducible in this animal and only hepatic cytochromes perform the demethylation of aminopyrine. Ischemia, varying from 90 to 200 minutes, generated a major decrease in the elimination of the 14CO2 and a marked change in the elimination curve. In this specific model it was not possible to assess survival of the animal by the ABT.
In a previous work on rat liver microsomes, we demonstrated that cytochrome P450 isozymes (P450) are engaged in the metabolism of RU486. In order to study the underlying mechanism at the molecular level, our investigations were shifted to a simplified system of cultured hepatoma cells which present a dissociation in the expression of distinct P450 coding genes. Our results show that Fao cells represent a convenient model to study both: (i) the degradation of RU486. Forms IIB1,2 and IIC7, which are present in Fao cells, may contribute to the demethylation of the molecule. Form IIIA, which has not been detected in Fao cells, is probably responsible for its oxidation in the liver; (ii) the effect of RU486 on the expression of P450 enzymes. Unlike other steroids (dexamethasone and pregnenolone 16 alpha-carbonitrile), RU486 does not induce P450 activity but inhibits the inducing activity of other agents such as dexamethasone and also phenobarbital. These findings may be important for the therapeutic use of RU486 since its inhibitory effect on P450 activity may be at the origin of drug interactions by modifying the endogenous hormonal status.