PubMed · 239542
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J B Schenkman, I Jansson. 1975. Interaction between microsomal electron transfer pathways.. https://doi.org/10.1007/978-1-4615-9026-2_28
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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 effects of a milk diet on gastric acid secretion of rats fed raw bovine milk for 4 days were examined using dispersed gastric cells. Parietal cell acid secretion was estimated by the accumulation of 14C-aminopyrine (AP), an index of secretory function. Basal AP accumulation was significantly increased (60%) by the milk diet. There was a marked upward shift in the dose-response curve of histamine (HA; 10(-8) to 10(-3) M) in milk-fed rats, indicating enhanced sensitivity of parietal cell-H2 receptor to exogenous HA. In contrast, the dose-dependent inhibition of HA-induced AP accumulation by prostaglandin (PG) E2 was significantly reduced, indicating that the parietal cells of milk-fed rats were less sensitive to exogenous PGE2. The PGE2 content of bovine milk was low (less than 20 pg/ml), but the production of endogenous PGE2 by the gastric cells was dramatically increased by the milk diet and exhibited maximal control production rate in the presence of 10 microM arachidonic acid. The increased responsiveness to histamine and the decreased responsiveness to PGE2 indicated that the milk diet induced low histamine and high PGE2 availability in the vicinity of the parietal cell basolateral membrane. This regulation, which involves stimulation of PGE2 production in the gastric mucosa, may underly the inhibition of acid secretion observed in vivo in chronically milk-fed adult rats.
The effects of the specific H3 agonist (R)-alpha-methylhistamine (alpha-MeHA) and the specific H3 antagonist thioperamide were examined on histamine release and acid secretion [( 14C]-aminopyrine (AP) accumulation) by isolated rabbit gastric glands. Thioperamide significantly enhanced basal histamine release from the glands (+50% at 30 min for 10(-7) M thioperamide; P less than 0.01), and this increase was prevented by alpha-MeHA. Histamine-elicited AP accumulation was increased by 18% (P less than 0.05) by 10(-7) M thioperamide and decreased by 70% (P less than 0.01) by 10(-6) M of the H2 antagonist ranitidine. Thioperamide alone significantly enhanced AP accumulation in a dose-dependent manner, whereas alpha-MeHA had no effect of its own on this accumulation. Thioperamide stimulation of basal AP accumulation was not modified by ranitidine but was 50% decreased by alpha-MeHA. Furthermore, carbachol-induced AP accumulation was decreased by alpha-MeHA and increased by thioperamide; the latter effect was not blocked by ranitidine. These findings support that H3 receptors pharmacologically distinct from H2 receptors are involved in the regulation of histamine-stimulated acid secretion. They further suggest that these gastric H3 receptors occur in the gastric glands as 1) H3 autoreceptors located on the histamine-secreting cells and acting to downregulate histamine release from these cells and 2) H3 (or H3-like) receptors located on the parietal cell and regulating in a negative manner the acid secretory process.