Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities.
Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase and has been approved for the treatment of nonsmall cell lung cancer refractory to established cancer treatments. Several cases of adverse hepatic and pulmonary events have been reported, which led to discontinuation of therapy. While the mechanism of toxicity remains unknown, we present evidence that gefitinib accumulates in the liver and lung, and it can be bioactivated in hepatic, intestinal, and pulmonary microsomes to form a reactive metabolite. The reactive metabolite was trapped by the peptide mimetic GSH, indicating that the metabolite was sufficiently reactive to bind to the cysteine groups of proteins. Two cytochrome P450-dependent gefitinib-GSH adducts were detected, and P450 1A1 and 3A4 were found to be the major enzymes responsible for adduct formation. The mechanism of bioactivation is proposed to involve oxidative defluorination of gefitinib to form a reactive quinone-imine. Clinical reports have noted an increase in adverse pulmonary events with patients who continued smoking. Consistent with the clinical toxicology data, a 12-fold increase in GSH adduct formation was detected in human pulmonary microsomes from smokers over nonsmokers, in agreement with P450 1A1 being induced by cigarette smoke.
Translational Research Institute and Department of Molecular Therapeutics, Scripps Florida, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Xiaohai
X
Li
Theodore M
TM
Kamenecka
Michael D
MD
Cameron
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D001711:Biotransformation; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity
D000970:Antineoplastic Agents; D011799:Quinazolines; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D066246:ErbB Receptors; D005978:Glutathione; D000077156:Gefitinib