Tetracyclines are well known broad spectrum antibiotics, bind with macromolecules (serum albumin and DNA). The higher binding affinity of tetracyclines for macromolecules in the body is implicated in drug stability and potency with a potential risk of macromolecular damage due to intracellular accumulation of tetracyclines. Photo- oxidation of TCs produces reactive oxygen species. Reactive oxygen species not only damage the protein but also induce strand breaks in DNA. Direct binding of tetracyclines with DNA, inducing the conformational changes, and the concomitant reduction of Cu(II), involving the formation of free radicals contribute for the strand breakage. There by indicating the essential role of hydroxyl radicals in the DNA breakage in addition to the methylation at N-3 and N-7 position of purine (A&G) which resulted mismatched of the base pairs. Thus in addition to the formation of strand breaks, the methylation of DNA bases by tetracyclines is also potentially mutagenic.