ahh…let me see if i can summarize this…tomorrow ill perfect it and put in all the references…still i miss one connection which i couldn’t find anywhere: finasteride and foxa2
So… Consider a person with a rare subset of polimorphisms on several steps of the liver detoxification process. Let’s say:
Phase I: -/- for CYP2D6 (this leads to increased estrogen)
Phase II: -/- for GSTO1 (this metabolises a finasteride metabolite), -/- for UGT1A3(this metabolises a finasteride metabolite’s metabolite)
Others: -/- for Pregnane X Receptor (which I am btw…this is affected by fin in high dosages), -/- for SOD2 (this leads to increase of super oxide, which is a ROS), Methylation block SNPs
This very unlucky person, takes a few mgs of finasteride:
Finasteride------------->Carboxy-Finasteride---------------->Omega Oic Finasteride------------------>Omega Oic Finasteride Glucuronide
____________CYP3A4_______________________GSTO1__________________________UGT1A3
Omega Oic Finasteride Glucuronide is found in human bile.
GSTO1 reaction takes place in the mitochondria of hepatocytes. GSTO1 generates ROS.
In a person with mitochondrial detoxification polimorphisms. In this case lets consider SOD2. This leads to impaired reduction of Super Oxide because of low presence of Super Oxide Dismutase. This directly leads to higher presence of Super Oxide because it’s not being reduced properly and Super Oxide is a ROS. So this leads to increase in ROS in the mitochondria.
SOD2 -/- -->Impaired reduction of Super Oxide–>ROS accumulation in Mitochondria–>Imbalance between Antioxidats/ROS->Oxidative stress ----> Mytochondrial Dysfunction
Increased ROS in the mitochondria will decrease glutathione. This will contribute to a depletion of glutathione.
Methylation blocks will contribute to the person’s inability to replenish glutathione properly in order to go on with the correct metabolism of finasteride.
Finasteride is an inducer of GST pi in the prostate, which means it probably increases ROS and this is a compensatory mechanism. Could be that this happens as well in the liver. If so, it means finasteride increases ROS in the liver.
Increased ROS mitochondria------->Decreased Glutathione
Methylation Blocks------------------>Decreased Glutathione
Finasteride induces ROS-----------.>Decreased Glutathione
Decreased Glutathione----------------------------------------> Depleted glutathione
given enough time leads to
Depleted Glutathione------------>Problems in Krebs Cycle
leads to
A dysfunctional mitochondria cross talks with Endoplasmatic Reticulum and indirectly makes it elevate the generation of ROS. This leads to ER Stress which is involved in thousands of gene changes!!!
A dysfunctional mitochondria will create an accumulation of Carboxy Finasteride.
A high level of Carboxy Finasteride maybe (or finasteride itself???) is the factor that makes high dosage finasteride inhibit 5beta reductase.
5 beta reductase inhibition inhibits Pregnane X receptor. This in turn leads to lowered CYP3A4 expression (maybe this is helpful??)
5 beta reductase inhibition impairs bile acid synthesis.
Glucocorticoid receptor is involved in a cross talk with Pregnane X Receptor. So that dexamethasone is modulating PXR as well as GCR.
High levels of Carboxy Finasteride–>inhibition of 5beta reductase–>inhibition of PXR–>decrease of CYP3A4—>accumulation of finasteride
High levels of Carboxy Finasteride–>inhibition of 5beta reductase–>impaired bile acid synthesis---->impaired bile flow—>high bilirubin
UGT1A3 mutations can also lead to impaired bile flow which lead to high bilirubin.
Could be that a Foxa2 defect is present as well and this will lead to Bile acid homeostasis dysregulation lead to ER Stress.
Bile Acid Problems, Homeostasis Dysregulation ------------------> ER Stress
lead to
Accumulation of finasteride together with CYP2D6 -/-, will lead to higher estrogen. Higher estrogen is associated with cholestasis. Highish concentrations of finasteride in rats, sometimes leads to leydig cell hyperplasia.
ER stress ties in with the Dolichol Deprivation Theory made by TNTW, which in turn ties in with 5AR3 inhibition.
Dolichol Deprivation Theory (due to inhibition of 5AR3??)–>UnfoldedProtein Response problem—>ER Stress
ER Stress leads to Drug Induced Liver Injury. This leads to systemic ROS production and systemic oxidative stress state.
Over time the drug exits the system, and the liver recovers. But maybe somewhere along the above process of damage, some organs were damaged, some genes methylated due to ER stress and/or hormonal changes, and mitochondrias become dysfunctional, leading to a host of problems. The PXR is involved with glucocorticoids as well and maybe this lead to the adrenal problems. I won’t theorize so much more as this is obviously an impossible exercise with such few data. I will perfect this as time goes by. I’m positive liver has had much influence in our condition and I will prove it is dysfunctional upon quitting.
Ideas on how to address this (this is not an advice on what to do! Follow this at your own risk and responsibility if you want):
----> PXR agonist
----> CYP inducer
----> UGT inducer
----> P450scc inducer (still have to check this one out too…forgot)
-----> Foxa2 inducer (impossible, there’s no data in this)
-----> ER stress killer
-----> Increasing Glutathione
-----> Helping dysfunction mytochondria
-----> Helping SOD2
-----> Possibly supporting the gut, pancreas, bile (???), adrenals, thyroid…
How to know if this is working out fine:
- Check LDL and HDL for positive changes
- Check D3 for positive changes
- Monitorize liver enzymes and bilirubin
- Check 3adiolG for increases and 3adiol for decreases
- check cortisol for normalization
- check improved thyroid function
- check improved testestore
- check improved estrogens
anyway, just my contribute. i’m not sure any of this makes any sense. But I will try it out. I hope when my vitamin D3 reaches 80, and my thyroid and cortisol normalise, I will solve my insomnia.
I will now buy supplements/drugs.