Kava Physiology Hepatotoxicity and flavokavain B
- Thread starter Blinkyrocket
- Start date
Palmetto
Thank God!
The puzzling thing about most or all of the studies on kava hepatotoxicity are that they use tumor cell lines to study hepatotoxicity, then they rave about the antitumor effects of flavokawains. This is not the general approach to studying other drugs. The effects on tumor cell lines need to separated from the effects on healthy liver cells before ANY conclusion can be made about liver hepatotoxicity. I used to do cancer research years ago. Now I work only in the clinic.
Zac Imiola (Herbalist)
Kava Connoisseur
lol 
dragonaut
Kava Curious
The explanation is probably that healthy liver cells are very expensive and annoying to grow (they need to come from a biopsy and stop dividing quite fast), whereas cancer cells are cheap and easy (they never stop dividing, i.e. they have cancer), so for researchers it is far easier to work with cancer/"immortalized" cell lines.
Regarding the anticancer effect of flavokavains, I must admit that I am not too optimistic. Their mode of action is most likely inhibition of glycolysis by alkylation of some of the key enzymes, which in turn leads to apoptosis. This is a fairly well-known mechanism, see e.g. https://en.wikipedia.org/wiki/Iodoacetic_acid#Possible_cancer_therapy
If this is indeed the mechanism, it would explain the general toxicity as well as the anticancer effect (cancer cells are often more glycolytic and thus more sensitive to these alkylators).
Palmetto
Thank God!
Perhaps inhibition of glycolysis is one mechanism of the antitumor effect of flavokawains, but apparently, it is not the only one. From a quick search, here is an article that describes numerous mechanisms that flavokawain B affects tumor proliferation/metastasis/and other effects. http://link.springer.com/article/10.1186/s12906-016-1046-8
So many different pathways are mentioned, that it is highly unlikely to result from simply inhibition of glycolysis.
dragonaut
Kava Curious
You're right, there's a lot of stuff going on. They are looking at gene expression and a lot of proteins get up- or downregulated, however there must be an initial event/mechanism that causes this. Given that flavokavain is an alkylator, it seems likely to me that alkylation of an active site cysteine (such as those in glycolytic enzymes) is the initiator. Many of the proteins they see upregulated are involved in the apoptosis pathway. However, alkylators are notoriously unspecific, so it is very likely that there are several targets and thus several mechanisms.
Here's a bit of information on GAPDH, which I think is the most likely target. When it gets modified, it has a variety of downstream - most notably apoptosis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383849/
Here's a bit of information on GAPDH, which I think is the most likely target. When it gets modified, it has a variety of downstream - most notably apoptosis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383849/