We had an important discovery: PPARα directly regulates expression and activity of CYP3A4, the major drug metabolizing P450 enzyme in humans. (Klein et al, CPT, 2012; Thomas et al, Mol Pharmacol, 2013). Several other important ADME genes seem to be regulated by PPARa.
I would like to ask the fans and experts in this field:
- Could PPARa be a mediator of connection between lipid/energy and drug metabolism?
1) is someone aware of clinical data on PPARa k.o. (or knock-in) mice with de-regulated detoxification of xenobiotics?
2) Could be that bile acids as substrates of CYP3A4 act as potential endogenous ligands of PPARa?
3) Are there any clinical trials available on influence of nutritional status on drug biotransformation capacity?
Article Direct Transcriptional Regulation of Human Hepatic Cytochrom...
Dear Maria,
this is an excellent question. I work in the university hosptal with focus on drug-induced liver injury. The best information I can provide is on the third part of your question:
Part 1: I'm sorry but I'm not aware of such data
Part 2: Bile acids play a role in liver regeneration (http://www.ncbi.nlm.nih.gov/pubmed/16614213) via the FXR. PPARa is a target gene of FXR (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440314/) and there are data suggesting that also direct interaction between FXR and CYP3A Genes exists:
http://journals.lww.com/jpharmacogenetics/Abstract/2004/10000/Regulation_of_CYP3A4_by_the_bile_acid_receptor.1.aspx). Taken together, there is evidence supporting the hypothesis that bile acids interact with PPARa and CYP3A4, yet I cannot give information wether there is a direct interaction between bile acids, PPARa and CYP3A4 or if FXR plays the more important role.
Part 3: In fact there is evidence that drug metabolism is altered in obese patients (http://www.ncbi.nlm.nih.gov/pubmed/22448619), with lower CYP3A4, higher UGT and CYP1A2, 2C), 2C19 and 2D6. Yet this requires further studies.
Additionally, there is evidence for altered toxicity of drugs by nutritional status:
1) low BMI inceases the risk for nevirapine hepatotoxicity (http://jid.oxfordjournals.org/content/191/6/825.short)
2) fasting (and alcohol) increase acetaminophen hepatotoxicity (http://jama.jamanetwork.com/article.aspx?articleid=384537)
3) Data from rats point in a similar direction: obesity increases liver damage by APAP (http://www.ncbi.nlm.nih.gov/pubmed/22647274)
I hope I could provide you some useful information and I would be very interested to have updates on your very interesting research
best regards
andreas
Dear Andreas,
thank´s a lot for your essential comments!
An issue of liver toxicity is certainly another dimension which we also want to include in our studies. It would be definitely of benfit for us to collaborate with you on this topic.
Dear Maria,
this would great, I'll send you an email
best regards andreas
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