In vivo protection of DNA damage associated apoptotic and necrotic cell deaths during acetaminophen-induced nephrotoxicity, amiodarone-induced lung toxicity and doxorubicin-induced cardiotoxicity by a novel IH636 grape seed proanthocyanidin extract

Grape seed extract, primarily a mixture of proanthocyanidins, has been show n to modulate a wide-range of biological, pharmacological and toxicological effects which are mainly cytoprotective. This study assessed the ability o f IH636 grape seed proanthocyanidin extract (GSPE) to prevent acetaminophen (AAP)-induced nephrotoxicity, amiodarone (AMI)-induced lung toxicity, and doxorubicin (DOX)induced cardiotoxicity in mice. Experimental design consis ted of four groups: control (vehicle alone), GSPE alone, drug alone and GSP E;drug. For the cytoprotection study, animals were orally gavaged 100 mg/Kg GSPE for 7-10 days followed by i.p. injections of organ specific three dru gs (AAP: 500 mg/Kg for 24 h; AMI: 50 mg/Kg/day for four days; DOX: 20 mg/Kg for 48 h). Parameters of study included analysis of serum chemistry (ALT, BUN and CPK), and orderly fragmentation of genomic DNA (both endonuclease-d ependent and independent) in addition to microscopic evaluation of damage a nd/or protection in corresponding PAS stained tissues. Results indicate tha t GSPE preexposure prior to AAP, AMI and DOX, provided near complete protec tion in terms of serum chemistry changes (ALT, BUN and CPK), and significan tly reduced DNA fragmentation. Histopathological examination of kidney, hea rt and lung sections revealed moderate to massive tissue damage with a vari ety of morphological aberrations by all the three drugs in the absence of G SPE preexposure than in its presence. GSPE+drug exposed tissues exhibited m inor residual damage or near total recovery. Additionally, histopathologica l alterations mirrored both serum chemistry changes and the pattern of DNA fragmentation. Interestingly, all the drugs, such as, AAP, AMI and DOX indu ced apoptotic death in addition to necrosis in the respective organs which was very effectively blocked by GSPE. Since AAP, AMI and DOX undergo biotra nsformation and are known to produce damaging radicals in vivo, the protect ion by GSPE may be linked to both inhibition of metabolism and/or detoxific ation of cytotoxic radicals. In addition, its' presumed contribution to DNA repair may be another important attribute, which played a role in the chem oprevention process. Additionally, this may have been the first report on A MI-induced apoptotic death in the lung tissue. Taken together, these events undoubtedly establish GSPE's abundant bioavailability, and the power to de fend multiple target organs from toxic assaults induced by structurally div erse and functionally different entities in vivo.