| Objective:1. Z-ligustilide is the main active ingredient in supercritical fluid extract (SFE) of Angelica Sinensis reaching a propotion of 42.21 ± 1.78%(m/m). In our previous studies, we demonstrated the intensive biological activity of Z-ligustilide. However, the efficacy of Z-ligustilide was limited due to its instability and tendency of isomerization and degradation. This paper aimed to examine the metabolic behaviours after oral administration and provide a therotical basis for further research and development of oral preparations of SFE.2. Anti-oxidation and anti-inflammtion are two main stratagies for chemoprevention. In this paper phenolic acid (PA) and SFE was choosen as anti-oxidants and anti-inflammatory agent respectively for chemopreventive experiments. Our research is amed to investigate the role of these two stratagies playing in the process of development of cancer, try to revearl the mechanism, and contribute the data support for development of Angelica preparations.Methods:1. Metabolism of Z-ligustilide in gastrointestinal track was investigated using rat gastriointestinal contents incubation tests to simulation the biological processes; The rat liver tissue homogenate post-mitochondrial supernatant (PMS) incubation tests was used to examine the metabolism of Z-ligustilde in liver; The concentration of Z-ligustilide in plasma of rat was examined and the concentration-time curves as well as pharmacokinetic (PK) parameters was obtained after oral administration of SFE or Z-ligustilide. The metabolite of Z-ligustilide in plasma was also detected.2. AOM/DSS Chronic inflammation associated conlonrectal cancer modle in mice was adopted. Using PA and SFE of Angelica in different stage of cancer development, factor analysis of cancer macroscopic characters and histopathological examination was performed to determine cancer development. Immunohistochemistry (IHC) and Western Blot (WB) tests were conducted for determination the inflammation, oxidative damage, cell proliferation and apoptosis, and investigation of mechamism of chemoprevention.Results:1. Gastrointestinal environments could cause the degradation of Z-ligustilide regardless SFE or Z-lisustilide was administrated. Z-ligustilide was rapidly absorbed into blood and liver was the main metabolic organ. Within 4hours most part of Z-ligustilide was metabolized (80.02%); PK studies showed that Z-ligustilide was absorbed rapidely (Tmsx=19.20 ± 15.26/17.43 ±11.40 min), extensively distributed (Vd/F=240.92 ± 76.12/339.53 ± 65.37 L · min-1), limination rapidly (CL=0.96±0.16/1.24 ± 0.21 mL · min-1 · kg-1). Though the coexistent components of Z-ligustilide in SFE could affect the absorption and metabolim of Z-ligustilide, a high level of the plasma concentration could not be sustained, and the low bioavailability was not changed. So the further pharmaceutic processing is also warranted in the development of SFE for chemoprevention of colorectal cancer.2. In the early stage of modeling process, anti-oxidation could effectively inhibit development of cancer in AOM/DSS model. As well as in the later stage of modeling process, anti-inflammation could limit the spread of chronic inflammation and affect the inflammatory response in tumour microenvironment to play a role in chemoprevention. It is noteworthy that development of cancer was not surpressed, but been accelerated versus control group after intervention of anti-oxidation in the later stage of modeling process. IHC and WB results showed that intervention of anti-oxidation in later stage of modeling process indeen decreased the index of DNA damage in tumour tissue, however, the expression of tumour suppressor gene p53 was downregulated, and apoptosis was also suppressed. So, as for the mult-step process of cancer development, anti-oxidation and anti-inflammation should be used separatedly at different stage.
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