A NON-ANTIBACTERIAL CHEMICALLY-MODIFIED TETRACYCLINE INHIBITS MAMMALIAN COLLAGENASE ACTIVITY
A NON-ANTIBACTERIAL CHEMICALLY-MODIFIED TETRACYCLINE INHIBITS MAMMALIAN COLLAGENASE ACTIVITY
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DOI：
10.1177/00220345870660080401
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发表时间：
1987-08-01
影响因子：
7.6
通讯作者：
RAMAMURTHY, NS
中科院分区：
文献类型：
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作者：
GOLUB, LM;MCNAMARA, TF;RAMAMURTHY, NS
四环素类药物（包括半合成类似物、二甲胺四环素和强力霉素）被认为是牙周治疗中有用的辅助药物，因为它们抑制革兰氏阴性牙周病病原体。最近，这些抗生素被发现可以抑制哺乳动物胶原酶活性，这一特性也可能具有治疗价值。有人认为，四环素类药物的抗胶原酶特性与它们的抗生素功效无关。为了进一步推进这一假设，我们将盐酸四环素化学转化为其非抗菌类似物，去二甲氨基四环素。这种化学修饰的四环素（CMT），虽然不再是一种有效的抗生素，但被发现可以抑制部分纯化的人类类风湿滑膜组织和大鼠骨骺的胶原酶的体外活性。在一项初步的体内研究中，通过使成年雄性大鼠患糖尿病，可诱导皮肤和牙龈中胶原酶的病理性过量，口服CMT可显著降低这两种组织中胶原酶的过量活性。此外，CMT给药对这些大鼠的严重高血糖没有影响，但至少在一定程度上预防了糖尿病引起的体重、皮肤重量和皮肤胶原蛋白质量的损失；这些影响表明在该动物模型中缺乏毒性。在治疗以过度胶原溶解活性为特征的疾病方面，CMT比传统四环素有一个临床优势，即在长期使用期间不产生抗生素耐药微生物。然而，支持这一假设的临床试验的考虑必须等待进一步的实验室和广泛的毒性试验。
Tetracyclines (including the semi-synthetic analogues, minocycline and doxycycline) are considered useful adjuncts in peridontal therapy because they suppress Gram-negative periodontopathogens. Recently, these antibiotics were found to inhibit mammalian collagenase activity, a property which may also be of therapeutic value. It has been suggested that the anti-collagenase properties of the tetracyclines are independent of their antibiotic efficacy. To advance this hypothesis further, we chemically converted tetracycline hydrochloride to its non-antimicrobial analogue, de-dimethylaminotetracycline. This chemically-modified tetracycline (CMT), althouth no longer an effective antibiotic, was found to inhibit the in vitro activity of collagenase from partially purified extracts of human rheumatoid synovial tissue and rachitic rat epiphysis. In a preliminary in vivo study, pathologically-excessive collagenase in skin and gingiva was induced by rendering adult male rats diabetic, and the oral administration of CMT to these rats significantly reduced the excessive collagenase activity in both tissues. Moreover, CMT administration did not affect the severe hyperglycemia in these rats but did prevent, at least in part, the diabetes-induced loss of body weight, skin weight, and skin collagen mass; these effects suggest a lack of toxicity in this animal model. A proposed clinical advantage of CMT over conventional tetracyclines, in the treatment of diseases characterized by excessive collagenolytic activity, is the lack of development of antibiotic-resistant micro-organisms during prolonged use. However, the consideration of clinical trials to support this hypothesis must await further laboratory and extensive toxicity tests.