Enhancement of Chemical Activation via Radical-Dependent Mechanisms: An Emerging Concept in Chemical-Chemical Interactions.
Oxygen Radicals in Biology and Medicine 1989:739-744
Examples were given of chemical activation via radical dependent mechanisms and their pharmacologic and toxicologic implications were discussed. Studies were conducted using bleomycin-A2 (11116317) and butylated-hydroxytoluene (128370) (BHT). Bleomycin-A2, a glycopeptide antibiotic used in chemotherapy, is activated in the presence of iron and reactive oxygen species to an intermediate which can cleave DNA-deoxyribose, producing toxic base propenals. Enzymes associated with the endoplasmic reticulum or nuclear membrane catalyze this reaction. While the enhanced generation of activated bleomycin within tumor cells is beneficial, occurrence of this process in host cells is not. The administration of BHT results in pulmonary toxicity as reflected in damage to type-I alveolar cells. Microsomes from various animal tissues, including the lung, can enhance the activity of BHA. BHT is first converted to its radical intermediate and then to its electron reduced electrophilic species, BHT-quinone-methide. The subcutaneous administration of BHA resulted in an enhanced lung/body weight ratio indicating BHT induced lung damage.
NIOSH-Grant; Cancer; Drug-interaction; Metabolic-study; Antineoplastic-agents; Laboratory-animals; Pulmonary-system-disorders;
Environmental Health Sciences Johns Hopkins University 615 N Wolfe Street Baltimore, MD 21205
Simic-MG; Taylor-KA; Ward-JF; Sonntag-C;
Asthma and Chronic Obstructive Pulmonary Disease; Disease and Injury; Pulmonary-system-disorders;
Oxygen Radicals in Biology and Medicine
Johns Hopkins University, Baltimore, Maryland