Impaired hepatic and intestinal ATP-binding cassette transporter G5/8 was associated with high exposure of β-sitosterol and the potential risks to blood-brain barrier integrity in diabetic rats.
OBJECTIVE
Plant sterols are thought to treat hypercholesterolemia via inhibiting intestinal cholesterol absorption. The aim of this study was to evaluate the contribution of impaired ATP-binding cassette transporter G5/8 (ABCG5/8) expression by diabetes to the increased β-sitosterol (BS) exposure and impact of increased BS on integrity of blood-brain barrier (BBB).


METHODS
Basal BS level in tissues of streptozotocin-inducted rats and ABCG5/8 protein levels in liver and intestine were investigated; pharmacokinetics of BS was studied following oral dose; and primarily cultured rat brain microvessel endothelial cells (rBMECs) were used to study BS transportation across BBB and effect of BS on BBB integrity.


RESULTS
Diabetic rats showed greatly upgraded basal levels of BS in plasma, intestine, cerebral and hippocampus, accompanied by impairment of ABCG5/8 protein expression in liver and intestine. Pharmacokinetics studies demonstrated higher AUC0-48 and Cmax , and lower faecal recoveries of BS after oral administration, indicating enhancement of absorption or efflux impairment. In-vitro data showed increased ratio of BS/cholesterol in high levels BS-treated rBMECs was associated with increased BBB permeability of some biomarkers including BS itself.


CONCLUSIONS
Impaired ABCG5/8 protein expression by diabetes led to increase in BS exposure, which may be harmful to BBB function.
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Jia
J
Li
Xinting
X
Wang
Haiyan
H
Liu
Haifang
H
Guo
Mian
M
Zhang
Dan
D
Mei
Can
C
Liu
Lei
L
He
Li
L
Liu
Xiaodong
X
Liu
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D002199:Capillary Permeability; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012855:Sitosterols / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*
D018528:ATP-Binding Cassette Transporters; D012855:Sitosterols; C025473:gamma-sitosterol; D002784:Cholesterol
ATP-binding cassette transporter G5; ATP-binding cassette transporter G8; blood-brain barrier; diabetes; β-sitosterol