The increase in the use of herbal products, particularly in patients taking conventional medicine, has increased the likelihood of drug-herb interactions. Herbal products sold to the public are often not a single chemical compound, but rather a complex mixture of hundreds of different constituents. Human microsomal systems have been employed as a cost and time efficient approach to prospectively evaluate individual constituents for the potential for interactions with drug metabolizing enzymes. In fact, it has been shown that certain herbal constituents are capable of direct inhibition of drug metabolizing enzymes in this system. However, extrapolation of the drug interaction potential to cellular systems or whole organisms is often difficult because the preparation of microsomes necessitates the destruction of the integrity of the living cell and the physiologically relevant processes within. The primary goal of this dissertation research was to investigate the effect of herbal products on human hepatic drug metabolizing enzymes and transporters using primary cultures of human hepatocytes.
Cultured hepatocytes were exposed to the various herbal constituents acutely, to evaluate the direct effect on enzyme activity, or chronically, to evaluate the indirect effect on enzyme expression and subsequent activity. Additionally, in order to assess to scalability of our in vitro UGT1A results to humans, healthy human subjects were administered acetaminophen, a general UGT1A probe, before and after a 7-day course of milk thistle.
These data demonstrate that herbal constituents can directly inhibit enzyme activity but also influence activity by indirectly modulating gene expression. In the case of St. Johns wort, human hepatocytes showed that while constituents were capable of enzyme induction, inhibition also occurred. However, in vivo, it is the former that predominates over the latter. Furthermore, our predictions of interactions in vivo for St. Johns wort have been validated through a number of clinical studies. The case of milk thistle, however, proved more complex. While our in vitro data showed the possibility of drug interactions with several drug metabolizing enzymes, little effect was found in vivo. The latter demonstrates the value of consideration of the entire pharmacologic profile of an herb before conclusions about clinical relevance are made.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04152005-150515 |
| Date | 18 May 2005 |
| Creators | Komoroski, Bernard |
| Contributors | Raman Venkataramanan, Ph.D., Reginald Frye, Pharm.D., Ph.D., Paul Schiff, Ph.D., Stephen Strom, Ph.D., Samuel Poloyac, Pharm.D., Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04152005-150515/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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