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*work in progress* Cytochrome P450 (CYP) systems involved in breakdown of Poison/"Vitamin A"

NOTE:  I am putting this stuff here so I can come back to it. I have found that those who try to micromanage detox of anything by pushing various cytochrome systems tend to get into "paralysis by analysis", and quite often may make one thing worse while making another thing better. That is not what I'm after. I'm more after the Black Box results, things that show actual benefit first, then we go back and figure out the mechanisms.  If one takes any actions on the research below, you should know that I'm not comfortable with using the research below for any actions at this point.  I'm saving this for later...I find the PROBLEM first, then the SOLUTION(S), and LATER see if I can match up a plausible MECHANISM.  With health, obsessing over the mechanism first (and using that to guess at solutions) usually ends up in mistakes that have to be fixed later.  It is exactly the obsession with MECHANISMS in cell studies and short-term studies, while ignoring the long-term studies in the real world, that has led to the Poison/"Vitamin A" problem!!!

Cytochrome  P450 26 family

The role of CYP26 enzymes in retinoic acid clearance

"Retinoic acid (RA) is a critical signaling molecule that regulates gene transcription and the cell cycle. Understanding of RA signaling has increased dramatically over the past decades, but the connection between whole body RA homeostasis and gene regulation in individual cells is still unclear. It has been proposed that cytochrome P450 family 26 (CYP26) enzymes have a role in determining the cellular exposure to RA by inactivating RA in cells that do not need RA. The CYP26 enzymes have been shown to metabolize RA efficiently and they are also inducible by RA in selected systems. However, their expression patterns in different cell types and a mechanistic understanding of their function is still lacking. Based on preliminary kinetic data and protein expression levels, one may predict that if CYP26A1 is expressed in the liver at even very low levels, it will be the major RA hydroxylase in this tissue. As such, it is an attractive pharmacological target for drug development when one aims to increase circulating or cellular RA concentrations. To further the understanding of how CYP26 enzymes contribute to the regulation of RA homeostasis, structural information of the CYP26s, commercially available recombinant enzymes and good specific and sensitive antibodies are needed."

Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases.

"All-trans-retinoic acid (atRA) is an important signaling molecule in all chordates. The cytochrome P450 enzymes CYP26 are believed to partially regulate cellular concentrations of atRA via oxidative metabolism and hence affect retinoid homeostasis and signaling. CYP26A1 and CYP26B1 are atRA hydroxylases that catalyze formation of similar metabolites in cell systems. However, they have only 40% sequence similarity suggesting differences between the two enzymes. The aim of this study was to determine whether CYP26A1 and CYP26B1 have similar catalytic activity, form different metabolites from atRA and are expressed in different tissues in adults. The mRNA expression of CYP26A1 and CYP26B1 correlated between human tissues except for human cerebellum in which CYP26B1 was the predominant CYP26 and liver in which CYP26A1 dominated. Quantification of CYP26A1 and CYP26B1 protein in human tissues was in agreement with the mRNA expression and showed correlation between the two isoforms. Qualitatively, recombinant CYP26A1 and CYP26B1 formed the same primary and sequential metabolites from atRA. Quantitatively, CYP26B1 had a lower K(m) (19nM) and V(max) (0.8 pmol/min/pmol) than CYP26A1 (K(m)=50 nM and V(max)=10 pmol/min/pmol) for formation of 4-OH-RA. The major atRA metabolites 4-OH-RA, 18-OH-RA and 4-oxo-RA were all substrates of CYP26A1 and CYP26B1, and CYP26A1 had a 2-10-fold higher catalytic activity towards all substrates tested. This study shows that CYP26A1 and CYP26B1 are qualitatively similar RA hydroxylases with overlapping expression profiles. CYP26A1 has higher catalytic activity than CYP26B1 and seems to be responsible for metabolism of atRA in tissues that function as a barrier for atRA exposure."

CYP26B1

Control of retinoid levels by CYP26B1 is important for lymphatic vascular development in the mouse embryo.

https://www.ncbi.nlm.nih.gov/pubmed/24361262
"Here we identify a novel function for CYP26B1, an enzyme known to play a role in tissue morphogenesis by fine-tuning retinoic acid (RA) concentration, in regulating lymphangiogenesis. Cyp26b1-null mice, in which RA levels are elevated, exhibited an increased number of lymphatic endothelial progenitor cells in the cardinal veins, together with hyperplastic, blood filled lymph sacs and hyperplastic dermal lymphatic vessels."

CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells.

https://www.ncbi.nlm.nih.gov/pubmed/20606468
"CONCLUSION:  The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration."

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.

"The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression"

CYP26A1

Regulation of a highly specific retinoic acid-4-hydroxylase (CYP26A1) enzyme and all-trans-retinoic acid metabolism in human intestinal, liver, endothelial, and acute promyelocytic leukemia cells.

https://www.ncbi.nlm.nih.gov/pubmed/16194896
"The recently identified retinoic acid (RA)-metabolizing cytochrome P450RAI-1 (CYP26A1) has been implicated in accelerated metabolism and rapid clearance of all-trans-retinoic acid (ATRA)"

CYP2E1

Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P4502E1

https://www.gastrojournal.org/article/S0016-5085(01)50156-0/fulltext
"Background & Aims: Long-term and excessive ethanol intake results in decreased plasma and hepatic levels of retinoic acid (RA), the most active derivative of vitamin A. The decrease of RA by ethanol treatment has been proposed to be a cytochrome P450 enzyme (CYP)-dependent process. However, the role of the major ethanol-induced CYP, CYP2E1, in the metabolism of RA has not been defined.

Conclusions: Ethanol-induced CYP2E1 plays a major role in the degradation of RA, which may provide a possible biochemical mechanism for chronic and excessive ethanol intake as a risk for both hepatic and extrahepatic cell proliferation and carcinogenesis."

 

 

 

 

Dr. Garrett Smith, the "Nutrition Detective"
Licensed Naturopathic Physician (NMD) in Arizona
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