PMID- 11448637
OWN - NLM
STAT- MEDLINE
DCOM- 20010830
LR  - 20201208
IS  - 0027-5107 (Print)
IS  - 0027-5107 (Linking)
VI  - 495
IP  - 1-2
DP  - 2001 Aug 22
TI  - Micronuclei induction, cell cycle delay and apoptosis as markers of cellular 
      stress caused by ursodeoxycholic acid in human lymphocytes.
PG  - 1-9
AB  - Ursodeoxycholic acid (UDCA) is a bile acid (BA) used for cholesterol gallstone 
      dissolution. Since epidemiological evidence indicates that BAs can be involved in 
      the etiology of colorectal cancer, we investigated the effects of UDCA and its 
      physiologically produced taurine conjugate tauroursodeoxycholic acid (TUDCA) on 
      human lymphocyte cultures in terms of genetic damage in the form of micronuclei 
      (MN) production, cell cycle modifications and induction of apoptosis. With 
      respect to controls, treatment with UDCA (from 10 microg/ml) caused a 
      dose-related increase in MN, whereas TUDCA caused no significant increase (up to 
      1000 microg/ml). Fluorescence in situ hybridization (FISH) analysis using 
      pancentromeric probes suggested that UDCA exerts aneugenic activity. 
      Bromodeoxyuridine/Hoechst flow cytometry showed that both BA significantly 
      inhibit cell cycle progression (UDCA at 100 microg/ml, and TUDCA, more markedly 
      at 300-1000 microg/ml). Neither UDCA nor TUDCA affected induction of apoptosis, 
      as evaluated by the Annexin-V-Fluos assay. We conclude that UDCA is potentially 
      genotoxic. However, taking into account the characteristics of other 
      physiological BA, our findings are in line with the concept that long-term UDCA 
      treatment may be safely administered. The multi-assay approach reported here 
      could be useful in the toxicological evaluation of newly developed BA analogs as 
      candidates for pharmacological use.
FAU - Fimognari, C
AU  - Fimognari C
AD  - Department of Pharmacology, University of Bologna, Via Irnerio 48, 40126 Bologna, 
      Italy. fimognari@biocfarm.unibo.it
FAU - Nusse, M
AU  - Nusse M
FAU - Cesari, R
AU  - Cesari R
FAU - Cantelli-Forti, G
AU  - Cantelli-Forti G
FAU - Hrelia, P
AU  - Hrelia P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Mutat Res
JT  - Mutation research
JID - 0400763
RN  - 0 (Biomarkers)
RN  - 0 (Cholagogues and Choleretics)
RN  - 0 (Mutagens)
RN  - 516-35-8 (Taurochenodeoxycholic Acid)
RN  - 60EUX8MN5X (ursodoxicoltaurine)
RN  - 724L30Y2QR (Ursodeoxycholic Acid)
RN  - G34N38R2N1 (Bromodeoxyuridine)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Biomarkers
MH  - Bromodeoxyuridine/metabolism
MH  - Cell Cycle/*drug effects/physiology
MH  - Cells, Cultured
MH  - Cholagogues and Choleretics/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Flow Cytometry
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Lymphocytes/*drug effects/metabolism
MH  - Male
MH  - Micronucleus Tests
MH  - Mutagens/*toxicity
MH  - Taurochenodeoxycholic Acid/toxicity
MH  - Time Factors
MH  - Ursodeoxycholic Acid/*toxicity
EDAT- 2001/07/13 10:00
MHDA- 2001/08/31 10:01
CRDT- 2001/07/13 10:00
PHST- 2001/07/13 10:00 [pubmed]
PHST- 2001/08/31 10:01 [medline]
PHST- 2001/07/13 10:00 [entrez]
AID - S1383571801001978 [pii]
AID - 10.1016/s1383-5718(01)00197-8 [doi]
PST - ppublish
SO  - Mutat Res. 2001 Aug 22;495(1-2):1-9. doi: 10.1016/s1383-5718(01)00197-8.