Zac Imiola (Herbalist)
Kava Connoisseur
Title sais it all.
@verticity
@verticity
Does kava inhibit phase 2 metabolism?
- Thread starter Zac Imiola (Herbalist)
- Start date
verticity
I'm interested in things
I'm not a biochem expert, but I'll try. Maybe @Palmetto and @PepperyPyrone can help me out here too.
Short answer: I don't know if kava inhibits phase 2 metabolism, but at least some of the metabolites do go through phase 2 metabolism.
In general your liver's goal when it metabolizes something is to transform it into something that is water soluble, and won't readily be re-absorbed or react with anything. It does this by adding water soluble groups to it such as -OH (hydroxy) groups, and also bulking it up by attaching ionic molecules to it. Phase 1 metabolism refers to chemical changes caused mainly by Cytochrome P450 enzymes, such as hydroxylation, which increases water solubility. Then in Phase 2, conjugation reactions take place with large ionic molecules such as glucuronic acid or our old friend gutathione. Conjugation just means the ion attaches to the drug metabolite and bulks it up and makes it more water soluble. Ref: https://en.wikipedia.org/wiki/Drug_metabolism#Phase_II_.E2.80.93_conjugation
What about kava? Looking at kavain metabolism, for example, in this paper they found conjugated glucuronide (and sulfate) metabolites of kavain in people's urine, so that implies that Phase 2 metabolism is definitely happening with kavain. It is certainly happening with the other KLs and FKs too, because it seems to be a pretty universal thing.
https://www.gtfch.org/cms/images/stories/media/tk/tk71_2/Tarbah.pdf
But, like I said, that does not imply that phase 2 is inhibited, which would mean that drinking kava would cause phase 2 metebolism to get "maxed out" and thus be less effective for other things you take at the same time. So I actually don't know the answer to the question that you literally asked.
Short answer: I don't know if kava inhibits phase 2 metabolism, but at least some of the metabolites do go through phase 2 metabolism.
In general your liver's goal when it metabolizes something is to transform it into something that is water soluble, and won't readily be re-absorbed or react with anything. It does this by adding water soluble groups to it such as -OH (hydroxy) groups, and also bulking it up by attaching ionic molecules to it. Phase 1 metabolism refers to chemical changes caused mainly by Cytochrome P450 enzymes, such as hydroxylation, which increases water solubility. Then in Phase 2, conjugation reactions take place with large ionic molecules such as glucuronic acid or our old friend gutathione. Conjugation just means the ion attaches to the drug metabolite and bulks it up and makes it more water soluble. Ref: https://en.wikipedia.org/wiki/Drug_metabolism#Phase_II_.E2.80.93_conjugation
What about kava? Looking at kavain metabolism, for example, in this paper they found conjugated glucuronide (and sulfate) metabolites of kavain in people's urine, so that implies that Phase 2 metabolism is definitely happening with kavain. It is certainly happening with the other KLs and FKs too, because it seems to be a pretty universal thing.
https://www.gtfch.org/cms/images/stories/media/tk/tk71_2/Tarbah.pdf
But, like I said, that does not imply that phase 2 is inhibited, which would mean that drinking kava would cause phase 2 metebolism to get "maxed out" and thus be less effective for other things you take at the same time. So I actually don't know the answer to the question that you literally asked.
Last edited:
Zac Imiola (Herbalist)
Kava Connoisseur
From experience it seems to have that effect, such as sensitivity to other psychoactive's like caffeine and personally Ive taken so much kava tincture before I found this forum that I threw myself into this weird adrenal stuck state ... eventually I fixed it by having kava in water...
I found this extremely interesting back then and chalked it up to whole plant medicine being superior and must have supplied me with what was needed.
I'm wondering then if too much kavain or other Kls can get stuck without the corresponding water soluble compounds in kava like glutathione
I found this extremely interesting back then and chalked it up to whole plant medicine being superior and must have supplied me with what was needed.
I'm wondering then if too much kavain or other Kls can get stuck without the corresponding water soluble compounds in kava like glutathione
verticity
I'm interested in things
I think the sensitivity to caffeine is actually cause by inhibition of a certain isoenzyme (CYP2E1) involved in Phase 1 metabolism, which is known to happen with kava. CYP2E1 is involved with alcohol and acetaminophen metabolism, which is why we recommend avoiding alcohol and Tylenol with kava, but it also metabolizes theophylline, which is an active metabolite of caffeine--so I think that accounts for the increased jittery feeling you get with caffeine+kava.
There is that theory that the naturally occurring glutathione in kava can prevent it from being depleted in your liver. For some people kava can cause the liver enzyme GGT to be elevated, and some people say that means that glutathione must be depleted, but I don't think they have actually measured the glutathione levels directly to verify that.
Last edited:
PepperyPyrone
I'll have the pyrones with some pepper, please.
@Mrbinx69
Ahhhh good ol UGT. It transfers a glucuronic acid to a metabolite making it more water soluble and easier to excrete in urine. There is no order of events but a lot of time there is a CYP P450 priming prior to UGT metabolism. The benzodiazepines are a big target for example where P450 modifies first and then UGT. It seems like kava is a substrate for UGTs but probably not an inhibitor. Not that I have found. Most of the inhibitors are synthetic and used in lab experiments to determine UGT substrate preference. Milk Thistle is known to inhibit UGT. Here is a good review article. http://rusynlab.unc.edu/publications/course_data/UGTLecture,9.2011-Tox442.pdf
As far as kavalactones inhibiting the CYP P450 phase 1, as @verticity said it's well studied and known especially for 2E1, which explains the alcohol interactions and sensitivity plus the aldehyde flushing and rash reaction that is well documented. I think there also might be something there with inhibition of aldehyde dehase that works into this backup of alcohol metabolites but I have never been able to find anything, please let me know if you have run across this. Possibly even something there with alcohol dehase inhibition. As far as the other P450s the data is very scattered and I'm not sure I trust much of the contradictions. There seems to be decent evidence for 1A2, 2C19, and 2C9. Maybe some with 2D6 and 3A4. But like with any chemical you put into your system there are going to be drug/drug interactions mostly involving the P450 inhibition and induction. And it's all over the board, it's actually one of the biggest problems right now in pharmacogenomics is controlling for drug/drug interaction even when you understand a patients CYP genotype.
Here is a good review on kava and CYP inhibition.
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.1010.7304&rep=rep1&type=pdf
Last edited:
