PMID- 8129745
OWN - NLM
STAT- MEDLINE
DCOM- 19940412
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 47
IP  - 4
DP  - 1994 Feb 11
TI  - Chloroquine accumulation and alterations of proteolysis and pinocytosis in the 
      rat conceptus in vitro.
PG  - 679-88
AB  - The teratogenicity of chloroquine (CQ) has been hypothesized to result from its 
      effects on lysosomal function, specifically the ability of the visceral yolk sac 
      (VYS) to capture and degrade external macromolecules. Using the rat whole embryo 
      culture system, we evaluated the ability of CQ to accumulate in conceptual 
      tissues and its effects on aspects of VYS function known to be important in the 
      uptake and processing of nutrients. When CQ was added directly to the culture 
      medium, it was found to accumulate rapidly in conceptual tissues, particularly 
      the VYS. Tissue concentrations of CQ in the embryo proper reached approximately 
      10-fold those in the medium, whereas concentrations in the VYS exceeded by 
      100-fold the medium concentration within a 4-hr exposure on gestational day (GD) 
      10. Embryotoxic concentrations of CQ (10-30 microM) enhanced the activity of 
      lysosomal cysteine proteinases measured in vitro under optimum pH conditions in 
      both embryonic and VYS homogenates after a 26-hr treatment from GD 10-11. A 
      different pattern of response in enzyme activity was observed between embryos and 
      VYSs that could be attributed to the preferential accumulation of CQ in the VYS. 
      Nonembryotoxic concentrations of CQ (1-7.5 microM) induced a 
      concentration-dependent increase in VYS enzyme activity that peaked in 
      conceptuses exposed to 20 microM CQ (an intermediate embryotoxic concentration). 
      The enhanced cysteine proteinase activity was time dependent and appeared to 
      increase gradually in conceptuses exposed to 10-20 microM CQ during the 26-hr 
      culture period. This was in contrast to the rapid accumulation of CQ in 
      conceptual tissues seen on gestational day 10. Protein content in the VYS was 
      increased significantly after a 9-hr exposure of whole conceptuses to CQ (20 
      microM), indicating an inhibition of VYS proteolytic activity in situ. After 24 
      hr of exposure to 20 microM CQ, VYS protein content was not significantly 
      different from control, but embryonic protein was reduced significantly by 20%. 
      These observations are consistent with a model of reversible inhibition of VYS 
      proteolysis by CQ followed by a compensatory increase in lysosomal proteinase 
      activity. VYS fluid-phase pinocytosis was also assessed after CQ exposure and 
      found to be inhibited only in the highest CQ concentration tested (30 microM). 
      Lower concentrations of CQ that were still embryotoxic (10-20 microM) did not 
      affect VYS fluid-phase pinocytosis, suggesting that inhibition of this activity 
      is not primarily responsible for CQ embryotoxicity.
FAU - Ambroso, J L
AU  - Ambroso JL
AD  - Department of Environmental and Industrial Health, University of Michigan, Ann 
      Arbor 48109-2029.
FAU - Harris, C
AU  - Harris C
LA  - eng
GR  - ES 05235/ES/NIEHS NIH HHS/United States
GR  - ES 07062/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Proteins)
RN  - 886U3H6UFF (Chloroquine)
SB  - IM
MH  - Animals
MH  - Chloroquine/*metabolism/toxicity
MH  - Culture Techniques
MH  - Embryo, Mammalian/*metabolism
MH  - Enzyme Activation/drug effects
MH  - Female
MH  - Male
MH  - Pinocytosis/drug effects
MH  - Proteins/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Yolk Sac/*drug effects/metabolism
EDAT- 1994/02/11 00:00
MHDA- 1994/02/11 00:01
CRDT- 1994/02/11 00:00
PHST- 1994/02/11 00:00 [pubmed]
PHST- 1994/02/11 00:01 [medline]
PHST- 1994/02/11 00:00 [entrez]
AID - 0006-2952(94)90131-7 [pii]
AID - 10.1016/0006-2952(94)90131-7 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1994 Feb 11;47(4):679-88. doi: 10.1016/0006-2952(94)90131-7.