The effect of xenobiotic compounds on drug metabolising enzymes was assessed in ruminants; the development of an <i>in vivo </i>approach using a drug cocktail to measure specific enzyme families of phase I and II metabolism has been developed. Predictive clearances based on <i>in vitro </i>data from tolbutamide, phenacetin, chlorzoxazone, midazolam and oxazepam incubations were correlated with clearance determined <i>in vivo </i>(R<sup>2</sup>=<i> </i>0.695). A drug cocktail approach was used to assess the effect of plant secondary compounds on phase I and II enzymatic activities. This approach showed that phase I enzymes, e.g. CYP3A, can be affected by plant compounds, such as α-pinene or pyrrolizidine alkaloids. Additionally, due to carry over from one treatment period to the next, this experiment showed that interaction between plant secondary compounds can alter the overall effect of a single compound. Subsequently, <i>in vitro </i>experiments with hepatocytes or rumen microorganisms from sheep or goats, showed that pyrrolizidine alkaloids were not completely degraded in rumen fluid after 48h. Dose- and time-dependent toxicity of pyrrolizidine alkaloids to hepatocytes were observed. The magnitude of toxicity measured in goat and sheep hepatocytes was compatible with <i>in vivo </i>observations. Interaction between plant compounds observed <i>in vivo </i>was confirmed by <i>in vitro </i>assays. This concept of interaction between plant compounds was used to decrease the toxicity of pyrrolizidine alkaloids to hepatocytes. Exposure to certain plant compounds prior to the potentially toxic compounds could decrease pyrrolizidine alkaloid toxicity by acting on phase I or II enzymes. The mechanism of protection appears to be different between sheep and goats.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590983 |
| Date | January 2007 |
| Creators | Ronseaux, S. |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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