Acetaminophen (Tylenol) Decreases Respiration By Changing Cardiolipin Composition

haidut

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I posted a few threads recently on the negative effects of acetaminophen (Tylenol) on brain function and steroid response.
Acetaminophen (Tylenol) Exposure During Pregnancy Feminizes The Offspring
Acetaminophen raises serotonin/adrenaline, aspirin lowers it

User @Koveras also posted a thread along similar lines.
Acetaminophen In Pregnancy Linked To Austism, Possibly Through Serotonin

This study may have elucidated the mechanism of action through which acetaminophen enacts these negative effects. It seems that acetaminophen is one of the few chemicals known to change the lipid composition of cardiolipin, and it does so in a negative way. The overall effect is decrease in oxygen consumption and respiration and increase in beta-oxidation (fat oxidation). Perhaps the most important finding of the study is that cardiolipin composition is at least as important for metabolism as cardiolipin levels. Supplementing T3 and/or saturated (hydrogenated) fat / phosphatdylcholine (PC) is known to increase cardiolipin levels back to normal. However, even if levels cannot be brought back to normal just restoring proper cardiolipin composition should have a beneficial effect. One more reason to eat coconut oil and saturated PC :):

Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain. - PubMed - NCBI

"...Cardiolipin is known to be required for normal mitochondrial function. Therefore, we investigated the consequence of the reduction in L4CL/LO3CL ratio induced by acetaminophen (ApAP) on mitochondrial respiration and ATP production. MPCs treated with ApAP displayed reduced basal oxygen consumption (Fig. 2A) without affecting ATP level measured in intact cells (Fig. 2B)."

"...Respiratory rates measured in the presence of glutamate and malate as substrates were similar in ApAP-treated and untreated MPCs (Fig. 4A), indicating that electron entry through complex I is not affected by acetaminophen. Conversely, when feeding electrons into complex II using succinate as the respiratory substrate, ApAP treatment reduced oxygen consumption as compared with untreated cells (Fig. 4B). In contrast, MPCs treated with ApAP displayed a significant increase in oxygen consumption rate supported by palmitoylcarnitine (Fig. 4C). These data indicate that ApAP affects Complex II and ETF/QOR-supported respiration by shifting electron entry from complex II to the ETF/QOR pathway."

"...Our data show that CL remodeling causes a shift in electron entry from complex II to the β-oxidation electron transfer flavoprotein quinone oxidoreductase (ETF/QOR) pathway. These data demonstrate that electron entry in the respiratory chain is regulated by CL fatty acid composition and provide proof-of-concept that pharmacological intervention can be used to modify CL composition."

"...Our data show that ApAP, independently of an antioxidant effect, causes profound remodeling of CL fatty acid composition, which is associated with a modification of the electron transport path in the mitochondria. Importantly, we have found that ApAP modulates CL composition at concentrations within the therapeutic range in humans, and we demonstrate for the first time that a pharmaceutical agent can affect CL fatty acid remodeling. Although the molecular pathway prior to CL remodeling still needs to be identified, our results could be explained by enhanced CL biosynthesis, impaired CL degradation, and/or modification of acyl chain remodeling."

"...Loss of CL content, CL peroxidation, and changes in the CL acyl chain composition have been linked to a large variety of pathologies. Modifications of CL levels are associated with mitochondrial dysfunction and can have dramatic consequences on bioenergetics. CLs regulate mitochondrial functions through numerous mechanisms, including modification of respiratory complexes, membrane dynamics, supercomplex stabilization, and ATP synthase regulation. Most studies have focused on CL levels; however, recent evidence indicates that L4CL is important for complexes I and II activities by facilitating electron transfer through CoQ (Schwall et al., 2012 and Pöyry et al., 2013), suggesting that CL fatty acid composition may be as important as total CL levels.
 

Regina

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I posted a few threads recently on the negative effects of acetaminophen (Tylenol) on brain function and steroid response.
Acetaminophen (Tylenol) Exposure During Pregnancy Feminizes The Offspring
Acetaminophen raises serotonin/adrenaline, aspirin lowers it

User @Koveras also posted a thread along similar lines.
Acetaminophen In Pregnancy Linked To Austism, Possibly Through Serotonin

This study may have elucidated the mechanism of action through which acetaminophen enacts these negative effects. It seems that acetaminophen is one of the few chemicals known to change the lipid composition of cardiolipin, and it does so in a negative way. The overall effect is decrease in oxygen consumption and respiration and increase in beta-oxidation (fat oxidation). Perhaps the most important finding of the study is that cardiolipin composition is at least as important for metabolism as cardiolipin levels. Supplementing T3 and/or saturated (hydrogenated) fat / phosphatdylcholine (PC) is known to increase cardiolipin levels back to normal. However, even if levels cannot be brought back to normal just restoring proper cardiolipin composition should have a beneficial effect. One more reason to eat coconut oil and saturated PC :)

Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain. - PubMed - NCBI

"...Cardiolipin is known to be required for normal mitochondrial function. Therefore, we investigated the consequence of the reduction in L4CL/LO3CL ratio induced by acetaminophen (ApAP) on mitochondrial respiration and ATP production. MPCs treated with ApAP displayed reduced basal oxygen consumption (Fig. 2A) without affecting ATP level measured in intact cells (Fig. 2B)."

"...Respiratory rates measured in the presence of glutamate and malate as substrates were similar in ApAP-treated and untreated MPCs (Fig. 4A), indicating that electron entry through complex I is not affected by acetaminophen. Conversely, when feeding electrons into complex II using succinate as the respiratory substrate, ApAP treatment reduced oxygen consumption as compared with untreated cells (Fig. 4B). In contrast, MPCs treated with ApAP displayed a significant increase in oxygen consumption rate supported by palmitoylcarnitine (Fig. 4C). These data indicate that ApAP affects Complex II and ETF/QOR-supported respiration by shifting electron entry from complex II to the ETF/QOR pathway."

"...Our data show that CL remodeling causes a shift in electron entry from complex II to the β-oxidation electron transfer flavoprotein quinone oxidoreductase (ETF/QOR) pathway. These data demonstrate that electron entry in the respiratory chain is regulated by CL fatty acid composition and provide proof-of-concept that pharmacological intervention can be used to modify CL composition."

"...Our data show that ApAP, independently of an antioxidant effect, causes profound remodeling of CL fatty acid composition, which is associated with a modification of the electron transport path in the mitochondria. Importantly, we have found that ApAP modulates CL composition at concentrations within the therapeutic range in humans, and we demonstrate for the first time that a pharmaceutical agent can affect CL fatty acid remodeling. Although the molecular pathway prior to CL remodeling still needs to be identified, our results could be explained by enhanced CL biosynthesis, impaired CL degradation, and/or modification of acyl chain remodeling."

"...Loss of CL content, CL peroxidation, and changes in the CL acyl chain composition have been linked to a large variety of pathologies. Modifications of CL levels are associated with mitochondrial this dysfunction and can have dramatic consequences on bioenergetics. CLs regulate mitochondrial functions through numerous mechanisms, including modification of respiratory complexes, membrane dynamics, supercomplex stabilization, and ATP synthase regulation. Most studies have focused on CL levels; however, recent evidence indicates that L4CL is important for complexes I and II activities by facilitating electron transfer through CoQ (Schwall et al., 2012 and Pöyry et al., 2013), suggesting that CL fatty acid composition may be as important as total CL levels.
And take Mitolipin. But egads!, the hits keep coming with this garbage. For some reason, I am reminded of when tylenol had been laced with cyanide (the Chicago Tylenol Murders). It seems not much better without it.
 

meatbag

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@haidut So the predominant fatty acid is unsaturated linolieic 18:2 as a tetralinolieic structure and it gets changed to a "trilinolieic mono-oleic" (3:1 18:2 to 18:1), a structure which includes a more saturated (in this case specifically a monounsaturate) fatty acid chain. So the ideal state of the cardiolipin is a structure primarily composed of unsaturated fatty acids and when these fatty acid chains become more saturated it reduces electron transport? (Still thinking a shift towards more unsaturation like 20:4 arachadonic structure is bad). The acetaminophen treatment increased the composition towards a structure including more of the MUFA (LO3CL) and as you said had a negative effect on respiration in terms of oxygen consumption and electron transport. Is it a case of a specific ideal composition and a shift towards more saturated or unsaturated has a negative effect?

upload_2017-7-10_18-3-39.jpeg
 
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Regina

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Crap, I used to take so much of this stuff when I was growing up :( I would always go to the school nurse because I had a "headache" but really it was just because there were always cute girls in there and I could take a nap...Probably went a couple times a week for several years before they caught on and always the same prescription; two Tylenol, a water and some crackers.

@haidut So the predominant fatty acid is unsaturated linolieic 18:2 as a tetralinolieic structure and it gets changed to a "trilinolieic mono-oleic" (3:1 18:2 to 18:1), a structure which includes a more saturated (in this case specifically a monounsaturate) fatty acid chain. So the ideal state of the cardiolipin is a structure primarily composed of unsaturated fatty acids and when these fatty acid chains become more saturated it reduces electron transport? (Still thinking a shift towards more unsaturation like 20:4 arachadonic structure is bad). The acetaminophen treatment increased the composition towards a structure including more of the MUFA (LO3CL) and as you said had a negative effect on respiration in terms of oxygen consumption and electron transport. Is it a case of a specific ideal composition and a shift towards more saturated or unsaturated has a negative effect?

View attachment 5890
Meatbag, that is so adorable.
My next door neighbor is an Endodontist and gobbles them up like candy. (so do construction workers, aikido students, etc etc.....)
 

meatbag

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Tarmander

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if only my teachers had felt the same way..... and yeah i know what you mean at college walking down the halls all the bookbags are a jinglin', but its not bells, or even gum containers, its painkillers and adderall -_- this guy I used to lift with would pop a few before every workout and game haha

Nothing like amphetamines to make you feel great for 5-10 years...before the paranoia really sets in.:eek:
 

meatbag

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Nothing like amphetamines to make you feel great for 5-10 years...before the paranoia really sets in.:eek:

just because you're paranoid, don't mean they're not after you :lurking:
 
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Tarmander

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just because you're paranoid, don't mean they're not after you :lurking:but yeah i know quite a few people who have taken or take that stuff and I think the paranoia set in a lot faster than that unfourtenetly. Really changes people.
Any interesting stories you'd care to share about changes you saw?
 

meatbag

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Last edited:

Tarmander

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well yeah, two specific instances come to mind but I don't wanna divulge too many personal details about them, just wouldn't feel good about doing that. One friend it really just eventually made them go off the deep end, just one of the most crazy things I've seen someone who isn't clearly insane do. The others it was mostly just obvious personality changes and changes in the way they seemed to think; like their whole perspective shifted. Like they had reduced emotions or something.
I hear ya on not wanting to share more. It can be very helpful though to have personal stories of tragedy. We used to watch more tragedy to remind ourselves of what can happen.
 

haidut

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Crap, I used to take so much of this stuff when I was growing up :( I would always go to the school nurse because I had a "headache" but really it was just because there were always cute girls in there and I could take a nap...Probably went a couple times a week for several years before they caught on and always the same prescription; two Tylenol, a water and some crackers.

@haidut So the predominant fatty acid is unsaturated linolieic 18:2 as a tetralinolieic structure and it gets changed to a "trilinolieic mono-oleic" (3:1 18:2 to 18:1), a structure which includes a more saturated (in this case specifically a monounsaturate) fatty acid chain. So the ideal state of the cardiolipin is a structure primarily composed of unsaturated fatty acids and when these fatty acid chains become more saturated it reduces electron transport? (Still thinking a shift towards more unsaturation like 20:4 arachadonic structure is bad). The acetaminophen treatment increased the composition towards a structure including more of the MUFA (LO3CL) and as you said had a negative effect on respiration in terms of oxygen consumption and electron transport. Is it a case of a specific ideal composition and a shift towards more saturated or unsaturated has a negative effect?

View attachment 5890

When cardiolipin is composed mostly of saturated fat it results in uncoupled respiration. I don't think this is bad outcome and it is seen in very young children and babies. There needs to be some electron transport to generate ATP but being more on the uncoupled side is usually better (IMO) as higher temps usually mean better immune system function and better health in general.
 

Momado965

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@haidut Do you think t3 can also increase the number of mitochondria rather than just increase the number of cardiolipin levels?
 

haidut

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@haidut Do you think t3 can also increase the number of mitochondria rather than just increase the number of cardiolipin levels?

Absolutely, there are tons of studies on that. CO2, aspirin, quinones, MB, etc all have this effect as well.
 

Momado965

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Absolutely, there are tons of studies on that. CO2, aspirin, quinones, MB, etc all have this effect as well.

To make it simple. Coke, aspirin, t3, k2, and MB = more mitochondria in cells = more energy generated . Do you concur? :D
 

haidut

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Luann

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So...how does ibuprofen stack up? (Since aspirin isn't very helpful for aches and pains for some of our forum members...)
 

haidut

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So...how does ibuprofen stack up? (Since aspirin isn't very helpful for aches and pains for some of our forum members...)


Probably less dangerous than Tylenol but still increases risk of heart attacks when used chronically. I think it is OK if used twice a week, especially if aspirin is also used on alternate days.
 

Luann

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That's great information haidut. I appreciate you answering my question.
 
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