Chemically-modified tetracycline normalizes collagen metabolism in diabetic rats: a dose-response study.
An earlier study indicated that a chemically-modified non-antimicrobial tetracycline (4-de-dimethylaminotetracycline; CMT-1) can inhibit excess collagenase activity in the connective tissues of diabetic rats, however, the optimum oral dose and resulting serum concentration were not determined. In the current study, adult male Sprague-Dawley rats (body weight approx. 350 g) were made diabetic by streptozotocin injection and administered by oral gavage either 0, 1, 2, 5, or 10 mg CMT-1 per day. After 3 weeks of drug therapy, the rats were killed and gingiva, skin, and serum collected. The tissues were 1) extracted, partially purified and analyzed for collagenase activity using [3H-methyl] collagen as substrate and SDS-PAGE/fluorography; 2) extracted in neutral salt and dilute acid solutions (4 degrees C) to assess collagen solubility; and 3) analyzed for hydroxyproline to determine tissue (skin) collagen mass. Serum was analyzed for glucose and CMT-1 concentration, the latter by HPLC. Inducing diabetes dramatically increased both gingival and skin collagenase activity and reduced skin collagen mass by 69.8%. Increasing the oral dose of CMT-1 progressively increased the serum concentration of the drug from 0.6-6.5 micrograms/ml and progressively decreased the excessive collagenase activity in gingiva and skin (p < 0.01 vs untreated diabetics). Although skin collagen mass tended to be increased at all oral doses of CMT-1, only the 5 mg dose effect was statistically significant (p < 0.01). The diabetes-induced reduction in collagen solubility, a classic abnormality (reflecting excessive collagen crosslinking) of this disease, was also normalized by CMT-1 therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Yu
Z
Z
Department of Oral Biology & Pathology, SUNY, Stony Brook 11794.
Ramamurthy
N S
NS
Leung
M
M
Chang
K M
KM
McNamara
T F
TF
Golub
L M
LM
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005881:Gingiva / Q000201:enzymology; D006909:Hydroxyproline / Q000032:analysis; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000201:enzymology; D012995:Solubility; D013329:Structure-Activity Relationship; D013752:Tetracycline / Q000008:administration & dosage* / Q000627:therapeutic use
D061965:Matrix Metalloproteinase Inhibitors; C053450:4-des-dimethylaminotetracycline; D003094:Collagen; D013752:Tetracycline; D006909:Hydroxyproline