The Liver and Finasteride

[tim1911]

@martinM

Someone else can jump in but I think finasteride is primarily a 5 Alpha Reductase type 2 inhibitor. I think it inhibits other enzymes also but not primarily.

In addition to blocking the 5-alpha reductase enzyme, finasteride is a competitive inhibitor of the 5-beta reductase type 2 enzyme.

en.wikipedia.org/wiki/Finasteride

ncbi.nlm.nih.gov/pubmed/19515843

[tim1911]

[Size=4]Inhibitory activity of isomers of bexlosteride on human steroid 5-beta-reductase: Virtual screening & molecular docking study
[/size]

NOTE : bexlosteride = Bexlosteride (LY-191,704) is a potent and noncompetitive inhibitor of the enzyme 5α-reductase related to finasteride and dutasteride.

Human steroid 5beta-reductase (aldo-keto reductase (AKR) 1D1) catalyzes reduction of Delta (4)-ene double bonds in steroid hormones and bile acid precursors. 5beta-reductase is responsible for generating 5beta-pregnanes, which are natural ligands for the pregnane-X receptor (PXR) in the liver. PXR is involved in the induction of CYP3A4, which is responsible for the metabolism of a large proportion of drugs

registration.akm.ch/einsicht.php?XNABSTRACT_ID=138749&XNSPRACHE_ID=2&XNKONGRESS_ID=149&XNMASKEN_ID=900

So theres the first problem.

More about the Pregnane X Receptor

PXR is a nuclear receptor whose primary function is to sense the presence of foreign toxic substances and in response up regulate the expression of proteins involved in the detoxification and clearance of these substances from the body.

PXR is activated by a large number of endogenous and exogenous chemicals including steroids, antibiotics, antimycotics, bile acids, hyperforin, a constituent of the herbal antidepressant St. John’s Wort, and many other herbal compounds.

Like other type II nuclear receptors, when activated, it forms a heterodimer with the retinoid X receptor, and binds to hormone response elements on DNA which elicits expression of gene products.[5]
One of the primary targets of PXR activation is the induction of CYP3A4, an important phase I oxidative enzyme that is responsible for the metabolism of many drugs.[3][4] In addition, PXR up regulates the expression of phase II conjugating enzymes such as glutathione S-transferase[7] and phase III transport uptake and efflux proteins such as OATP2 (SLCO2A1)[8] and MDR1 (ABCB1)

All from wiki.

Just a little about the "hormone response element.

Hormone-Receptor Binding and Interactions with DNA

Being lipids, steroid hormones enter the cell by simple diffusion across the plasma membrane. Thyroid hormones enter the cell by facilitated diffusion. The receptors exist either in the cytoplasm or nucleus, which is where they meet the hormone. When hormone binds to receptor, a characteristic series of events occurs:

-Receptor activation is the term used to describe conformational changes in the receptor induced by binding hormone. The major consequence of activation is that the receptor becomes competent to bind DNA.
-Activated receptors bind to “hormone response elements”, which are short specific sequences of DNA which are located in promoters of hormone-responsive genes. In most cases, hormone-receptor complexes bind DNA in pairs, as shown in the figure below.
Transcription from those genes to which the receptor is bound is affected. Most commonly, receptor binding stimulates transcription. The hormone-receptor complex thus functions as a transcription factor.

vivo.colostate.edu/hbooks/pathphys/endocrine/moaction/intracell.html

I wonder if this fits into what awor has found?

[tim1911]

The pregnane X receptor gene (PXR/NR1I2) regulates an array of genes involved in the response to xenobiotics.1,2 Dysregulation of this gene may critically influence intestinal barrier defence and susceptibility to inflammatory bowel disease (IBD).

ncbi.nlm.nih.gov/pmc/articles/PMC1860087/

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Results suggest that PXR strongly induces CYP3A4 gene transcription by interacting with HNF4alpha, SRC-1, and PGC-1alpha. PXR concomitantly inhibits SHP gene transcription and maximizes the PXR induction of the CYP3A4 gene in human livers.

Finasteride inhibits CYP3A4 due to 5b reductase, a PXR ligand, being inhibited by finasteride?

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Further more

Fasting induces PXR expression in liver

Thus we show that two fasting activated pathways PGC-1α and SIRT1 differentially modify PXR expression and function.

ncbi.nlm.nih.gov/pubmed/21933665

By reading the study the pxr is induced by energy sensors, so for this to take place no energy must be coming in. I read about a member who fasted, but still consumed mayple syrup, lemon juice etc. , this wont cut it unfortunately.

[tim1911]

[Size=4]Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor[/size]

Abstract

Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2). These genes control the metabolism (CYP3A subfamily) and
aspects of the pharmacokinetics (MDR1 and OATP2) of both endogenous and xenobiotic compounds. Since PXR is important in understanding the actions of endocrine disruptors (EDs), we determined the ability of suspected EDs to interact with PXR. In our study, 7
of 54 xenobiotics compounds interacted with PXR, including methoxychlor and benzophenone. All of the chemicals activated PXR in vitro and induced CYP3A mRNA in the male rat liver. In addition, CYP2C11 was also induced by some PXR agonists and converted
methoxychlor into xenoestrogen. These findings suggest that some EDs affect sex hormone receptor indirectly by induction of metabolic enzyme via PXR, to produce rapidly higher concentrations of effective metabolites, leading to disturbance of the endocrine system.

[Airborne]

I agree this looks to be are problem. Are there any test for this or would this fall under gene mapping also are there any therapeutic approaches for this? Nice find Tim

[tim1911]

@tim1911

[Size=4]Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor[/size]

Abstract

Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2). These genes control the metabolism (CYP3A subfamily) and
aspects of the pharmacokinetics (MDR1 and OATP2) of both endogenous and xenobiotic compounds. Since PXR is important in understanding the actions of endocrine disruptors (EDs), we determined the ability of suspected EDs to interact with PXR. In our study, 7
of 54 xenobiotics compounds interacted with PXR, including methoxychlor and benzophenone. All of the chemicals activated PXR in vitro and induced CYP3A mRNA in the male rat liver. In addition, CYP2C11 was also induced by some PXR agonists and converted
methoxychlor into xenoestrogen. These findings suggest that some EDs affect sex hormone receptor indirectly by induction of metabolic enzyme via PXR, to produce rapidly higher concentrations of effective metabolites, leading to disturbance of the endocrine system.

multidrug resistance 1 (MDR1),

Its ability to transport the above substrates accounts for the many roles of ABCB1 including:

-Regulating the distribution and bioavailability of drugs
-Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, and therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
-Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs
The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen
-The transport of compounds out of the brain across the blood-brain barrier
Digoxin uptake
-Prevention of ivermectin entry into the central nervous system
-The migration of dendritic cells
-Protection of hematopoietic stem cells from toxins.

organic anion-transporting peptide 2 (OATP2)

Organic anion transporters may carry bile acids as well as bilirubin over the basolateral membrane (facing sinusoids) in hepatocytes, as well as other anions for excretion in bile

.

The multidrug resistance 1 is regulated by the PXR,

These data suggest that PXR down-regulation could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance to them, in the treatment of endometrial cancer.

---

I think most people know about this,

[Size=4]Pregnane X receptor as a therapeutic target to inhibit androgen activity.[/size]

Abstract

The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that received daily injections of testosterone propionate by inducing the expression of cytochrome P450 (CYP)3As and hydroxysteroid sulfotransferase (SULT)2A1, which are enzymes important for the metabolic deactivation of androgens. In human prostate cancer cells, treatment with the PXR agonist rifampicin (RIF) inhibited androgen-dependent proliferation of LAPC-4 cells but had little effect on the growth of the androgen-independent isogenic LA99 cells. Down-regulation of PXR or SULT2A1 in LAPC-4 cells by short hairpin RNA or small interfering RNA abolished the RIF effect, indicating that the inhibitory effect of RIF on androgens was PXR and SULT2A1 dependent. In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone-dependent prostate cancer.

This theory has been round for a while on chrislers forum.

[Oscar]

@tim1911

This theory has been round for a while on chrislers forum.

Twas me! Ive already posted about this stuff ~1year ago.

[tim1911]

Sorry Oscar i didnt read it all, did notice you got banned though

Did you explore the possibility that our PXR is being under expressed?

IBD is common on this board,

A disease- and tissue-specific decrease in the expression of detoxification enzymes and ABC transporters was observed, which may be explained by a loss of PXR expression. Thus, dysregulation of xenobiotic metabolism and PXR activity in the gut is likely to contribute to the pathophysiology of UC.

PXR was underexpressed in colonic tissue of 7 out of 11 Crohn disease and in 4 out of 5 patients with ulcerative colitis.

Seems like things that can improve the situation activate the receptor, nystatin, antibiotics, steroids, fasting, bile acid.

[Oscar]

@tim1911

Sorry Oscar i didnt read it all, did notice you got banned though

Did you explore the possibility that our PXR is being under expressed?.

Posted it on this forum too viewtopic.php?f=33&t=5282&p=51677#p51677. In fact a websearch of this topic turns up quite a few of my ramblings!

Although the PXR may have been under-expressed whilst using Fin, it would now need to be over-expressed to prevent androgens from working.

[tim1911]

@Oscar

Although the PXR may have been under-expressed whilst using Fin, it would now need to be over-expressed to prevent androgens from working.

Would it though? There is a link between PXR and steroid hormone receptors, due to hormone metabolism.

So im wondering if an over expressed PXR desensitizes receptors to androgens, would an under expressed PXR over sensitize receptors to androgens.

You may have covered this already, i havent read all your posts.

@Oscar

In fact a websearch of this topic turns up quite a few of my ramblings!

Yes you are quite a star.

[tim1911]

Actually Oscar here is a mechanism where an under active PXR will directly effect the androgen receptor/gene expression, but it would have to mean 1 of 2 things

1. 5beta reductase did not regenerate properly
2. Finasteride was not metabolized properly and is being stored in the liver, continuing to inhibit enzymes in the liver.

When the PXR is activated, by 5beta reductase metabolites, it forms a hetero dimer with the retinoid X receptor, and binds to hormone response elements on DNA which elicits expression of gene products.

Substances or actions that activate the PXR - Antifungals, antibiotics, bile acids, fasting, steroids.

I assume these substances or actions are returning the PXR to homeostasis and not over expressing it (PXR) because according to above studies over expression is another problem in its self.

[martinM]

Many antifungals are competitive inhibitors of the cytochrome p450 enzyme family.

[Oscar]

@tim1911

Actually Oscar here is a mechanism where an under active PXR will directly effect the androgen receptor/gene expression, but it would have to mean 1 of 2 things

1. 5beta reductase did not regenerate properly
2. Finasteride was not metabolized properly and is being stored in the liver, continuing to inhibit enzymes in the liver.

When the PXR is activated, by 5beta reductase metabolites, it forms a hetero dimer with the retinoid X receptor, and binds to hormone response elements on DNA which elicits expression of gene products.

Substances or actions that activate the PXR - Antifungals, antibiotics, bile acids, fasting, steroids.

I assume these substances or actions are returning the PXR to homeostasis and not over expressing it (PXR) because according to above studies over expression is another problem in its self.

Most drugs (finasteride included) and androgens are inactivated and cleared by the same enzymes controlled by the PXR. These enzymes would now have to be over-expressed for androgens to be inactivated at a higher level than before. The two enzymes are p4503a4 and Sulta1 which scientists have confirmed can cause hypogonadism as a result of their over-expression (see the link i posted) - therefore even this idea is more plausable than awor’s ideas as it has some scientific backing!

However as most drugs (in fact virtually all xenobiotics) are cleared by these enzymes, i dont know why finasteride would be so special. 5b-reductase metabolites can be measured for in a blood test and already have been (see the 5a/5b metabolites results thread). The idea that finasteride is being 'stored in the ‘liver’ is not realistic and without any sort of backing.

[tim1911]

@Oscar

(see the 5a/5b metabolites results thread)

Im not sure what you concluded in this thread, did you think beta metabolites were high or low?

@Oscar

Most drugs (finasteride included) and androgens are inactivated and cleared by the same enzymes controlled by the PXR.

@Oscar

However as most drugs (in fact virtually all xenobiotics) are cleared by these enzymes, i dont know why finasteride would be so special.

Yes you are right.

Human steroid 5beta-reductase (aldo-keto reductase (AKR) 1D1) catalyzes reduction of Delta (4)-ene double bonds in steroid hormones and bile acid precursors. 5beta-reductase is responsible for generating 5beta-pregnanes, which are natural ligands for the pregnane-X receptor (PXR) in the liver. PXR is involved in the induction of CYP3A4, which is responsible for the metabolism of a large proportion of drugs

I guess the question is what would happen if finasteride was not being metabolized properly, and possibly the steroid hormones.

This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.

Please tell me what you concluded about the 5beta metalobites.

[Oscar]

@tim1911

Please tell me what you concluded about the 5beta metalobites.

I gathered the information together, but im not educated on this subject enough to conclude anything. The 5alpha metabolites are sometimes low, thats about it.

Also, if SultA1 was over-expressed there may be a bias towards 3Adiol being conjugated with Sulfotransferases rather than Glucuronyl transferase, thus leading to low 3AdiolG (but higher 3AdiolS). A nice coincidence!, although I doubt any of this is really happening to us.

[tim1911]

Here is a liver detox profile of a member who took SP, maybe this shows something?

Liver detoxification profile results

Phase 1 : Caffeine clearance (0.5-1.8 ml/min/kg) 2.7 HIGH
When Phase 1 activity is high there is increased metabolic activity at the intermediate phase (before the molecules are presented to phase 2 for conjugation).This results in increased production of free radicals and the potential for secondary tissue damage.

Phase II : Glutathionation (5.6% - 11.4%) 5.4 LOW
Responsible for detoxification of : Pesticides , Paracetemol , Toxic metals , Penicillin , Tetracycline , Petroleum , Alcohol

Sulphation (16-36%) 30%
Glucuronidation (27-56%) 29%
Glycination (30%-53%) 31%

Ratios
Sulphate:Glucuronide (0.3 - 0.7) 1.0 HIGH
Reflects relationship between sulphate and glucuronide.

Phase 1:Sulphation (3.5-13.0) 9.1

Phase 1 : Glycination (1.3-3.5) 8.6 HIGH
Phase 1 : Glucuronide (1.9-4.2) 9.1 HIGH
These two ratios reflect the relationship between Phase I and these conjugation (detox?) pathways and will demonstrate whether the biochemical load from Phase 1 is high or low.

It would appear that something is in wrong. What do you think?

[Oscar]

@tim1911

It would appear that something is in wrong. What do you think?

Yeah i saw that. Looks like some sort of scam.

[tim1911]

I dont know, but if it is then there must be some sort of test which is legitamite to test this.

[tim1911]

Ok im with you now, we must have an over expressed pxr for this to be doing what it is doing.

We gain a tolerance to everything, not just androgens. In my experience PDE5i.

Pharmacokinetic Tolerance
Pharmacokinetic Tolerance - Also known as Dispositional tolerance: occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes.

It would appear that we have overactive phase 1 liver enzymes, which does correspond to the above detox profile

Phase 1 : Caffeine clearance (0.5-1.8 ml/min/kg) 2.7 HIGH

Which in turn has put to much pressure on phase 2 slowing it down.

Phase II : Glutathionation (5.6% - 11.4%) 5.4 LOW
Responsible for detoxification of : Pesticides , Paracetemol , Toxic metals , Penicillin , Tetracycline , Petroleum , Alcohol

This explain i personally have hang overs that last for days, explains why i gain tolerance to a pde5i in a day.

If we were gaining tolerance to just androgens it would be a different story, but its not, its everything.

A thought to what may have happened is 5beta reductase and 5alpha reductase regenerated at different rates.

[bluejaysfan]

Tim, do you have highish bilirubin? I believe that is also a symptom of slow phase 2 - Gilbert’s syndrome.

My doctor told me years ago I had GS. Maybe it’s due to what you’re saying… Over active phase 1.

I have tried calcium d glucarate before to speed up phase 2… Going to see what niacinamide does for me now, as it’s supposed to slow phase 1.