Inducible nitric oxide synthase-mediated decrease of intestinal P-glycoprotein expression under streptozotocin-induced diabetic conditions.
OBJECTIVE
P-glycoprotein (P-gp), one of the important drug-efflux pumps, is known to be affected by pathological conditions such as inflammation or infection. Recently, it is reported that high glucose or hyperglycemia can alternate P-gp expression levels at the blood-brain barrier or in the kidney, although the details are still unknown. Here, we analyzed the alteration of intestinal P-gp expression and function in the development of diabetes and elucidated the mechanisms.


METHODS
Type 1 diabetes was induced in male ddY mice by an i.p. injection of streptozotocin (STZ) (230 mg/kg). We analyzed ileal P-gp expression and function using Western blot analysis and an in situ closed loop method, respectively.


RESULTS
A significant reduction of P-gp expression level in ileum was found 9 days after STZ administration. In contrast, a remarkable decrease in P-gp function was observed on the 3rd and 9th days. Interestingly, nitric oxide synthase (NOS) activity in ilea was significantly increased on the 9th day. The decrease of P-gp expression levels observed on the 9th day was completely suppressed by L-N(G)-nitroarginine methyl ester (L-NAME), a broad range NOS inhibitor, or aminoguanidine, a specific inducible NOS (iNOS) inhibitor.


CONCLUSIONS
These results indicate the possibility that nitric oxide (NO), produced by iNOS in the ileum, is involved in the reduction of ileal P-gp expression under STZ-induced diabetic conditions.
Nawa
Ayaka
A
Department of Clinical Pharmacy, Kobe Gakuin University Faculty of Pharmaceutical Sciences, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
Fujita Hamabe
Wakako
W
Tokuyama
Shogo
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004326:Drinking; D004435:Eating; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D008297:Male; D008566:Membranes / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D014563:Urodynamics / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001786:Blood Glucose; D007328:Insulin; D020030:Nitric Oxide Donors; D052247:Nitric Oxide Synthase Type II; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases