The direct and indirect effects of herbal products on common drug metabolizing enzymes and drug transporters

2005 2005

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Abstract (summary)

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. John's 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. John's 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.

Indexing (details)

0491: Pharmacology
0419: Pharmacology
0572: Pharmaceuticals
Identifier / keyword
Health and environmental sciences; Pure sciences; Cytochrome P450; Drug metabolism; Drug transporters; Herbal
The direct and indirect effects of herbal products on common drug metabolizing enzymes and drug transporters
Komoroski, Bernard J., Jr.
Number of pages
Publication year
Degree date
School code
DAI-B 66/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780542311444, 0542311445
Venkataramanan, Raman
University of Pittsburgh
University location
United States -- Pennsylvania
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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