Effect of succinylacetone on heme and cytochrome P450 synthesis in ..
Heme and Porphyrin Metabolism Flashcards | Quizlet
Here we showed that FLVCR1a is essential for the maintenance of heme and iron homeostasis in the liver and that its function is strictly associated with the heme biosynthetic process that is crucial for the control of CYP activity.
Hepatic heme metabolism and cytochrome P450 in …
To test whether the main determinant for CYP expression/function was the size of heme pool or the rate of heme synthesis, both impaired in Flvcr1a-deleted liver, we treated wild-type mice with dexamethasone or Be(a)P alone or together with hemin, to mimic heme overload occurring in Flvcr1afl/fl;alb-cre mice, or with succinylacetone or DL-penicillamine, 2 inhibitors of heme biosynthesis. As expected, dexamethasone and Be(a)P treatment caused a marked increase in ALAS1 activity as well as in CYP expression/activity, and HO-1 expression/activity was only slightly induced (A and B). Hemin co-treatment significantly reduced hepatic ALAS1 activity, while increasing HO-1 expression/activity, compared with mice treated with dexamethasone or Be(a)P only (A and B). This correlated nicely with a reduced expression and activity of CYPs (B). Similarly, we observed that co-treatment with Be(a)P and the ALAS-inhibitor DL-penicillamine decreased ALAS activity as well as the expression and activity of CYP1A1 (A and B, right). Administration of succinylacetone, a heme synthesis inhibitor acting on 5-aminolevulinic acid dehydratase downstream of ALAS1, caused a feedback up-regulation of ALAS1 activity, as expected, but a decrease in CYP3A activity, as a consequence of reduced heme availability (A and B, left). We can conclude that the effect of heme overload on cytochrome function parallels that of heme synthesis inhibition, fostering the concept that cytochrome function is strictly associated to de novo heme production rather than to heme pool size itself.