A novel extract SB-300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human colonic epithelial cells.
An oligomeric proanthocyanidin (SP-303) extracted from the bark latex of the tree Croton lechleri (family Euphorbiaceae) is a potent inhibitor of cholera toxin-induced fluid accumulation and chloride secretion. The manufacturing process for SP-303 was optimized and simplified to produce an increased yield of the herbal extract. The novel extract (named SB-300) contained on average 70.6+/-7.2% SP-303 by weight (mean +/- S.D.; n=56 lots). Here, we describe the effectiveness of SB-300 on cAMP-regulated chloride secretion, which is mediated by the cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR) in human colonic T84 cells. Exposure of the apical surface to SB-300 blocked forskolin-stimulated Cl- secretion by 92.2+/-3.0% with a half-maximal inhibition constant (KB) of 4.8+/-0.8 microM. For SP-303, stimulated Cl- currents were decreased by 98.0+/-7.2 % and KB averaged 4.1+/-1.3 microM. There was no significant difference between the blocking kinetics of SP-303 and SB-300. Forskolin-stimulated whole cell Cl- currents were effectively blocked by extracellular addition of SB-300 (63+/-8.5%; n=3) and to a similar extent by SP-303 (83 +/- 0.6%; n=2; at 50 microM each). Both extracts inhibited a time- and voltage-independent Cl- conductance, which indicated the involvement of CFTR Cl- channels. We conclude that both SP-303 (used in Provir) and SB-300 (used in NSF Normal Stool Formula) are novel natural products that target the CFTR Cl- channel. SB-300 is a low cost herbal extract and may present a complementary and alternative medicine approach for the treatment of fluid loss in watery diarrhea.
Fischer
Horst
H
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.
Machen
Terry E
TE
Widdicombe
Jonathan H
JH
Carlson
Thomas J S
TJ
King
Steven R
SR
Chow
John W S
JW
Illek
Beate
B
D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects*; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000187:drug effects*; D029802:Croton; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D018408:Patch-Clamp Techniques; D008517:Phytotherapy; D024301:Plant Bark; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D010936:Plant Extracts; D019005:Cystic Fibrosis Transmembrane Conductance Regulator