Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile.
The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL) is approved for treatment of non-small-cell lung cancer. Numerous reports of ERL-associated toxicities are consistent with immune-mediated toxicity, including drug-induced hepatitis, interstitial lung disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Although the mechanism of toxicity has not been established, we present evidence that reactive intermediates are formed during the metabolism of ERL, which can covalently conjugate to the cysteine group of the peptide-mimetic GSH. Seven ERL-GSH conjugates were identified in incubations with hepatic microsomes. Cytochrome P450 (P450)-dependent adducts are proposed to be formed via reactive epoxide and electrophilic quinone-imine intermediates. In incubations of human liver microsomes, intestinal microsomes, pulmonary microsomes, and recombinant P450s, CYP3A4 was the primary enzyme responsible for the bioactivation of ERL; however, CYP1A1, CYP1A2, CYP3A5, and CYP2D6 were capable of catalyzing the bioactivation as well. During the metabolism of ERL, CYP3A4 and CYP3A5 are irreversibly inactivated by ERL in a time- and concentration-dependent manner. Inactivation was not dependent on oxidation of the ERL alkyne group to form a reactive oxirene or ketene, as shown by synthesizing analogs where the alkyne was replaced with a cyano group. CYP1A1, CYP1A2, and CYP2D6 were not inactivated despite catalyzing the formation of ERL-GSH adducts.
Li
Xiaohai
X
Translational Research Institute, Scripps Florida, the Scripps Research Institute, Jupiter, Florida 33458, USA.
Kamenecka
Theodore M
TM
Cameron
Michael D
MD
D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D011799:Quinazolines / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D065607:Cytochrome P-450 Enzyme Inhibitors; D011799:Quinazolines; D003577:Cytochrome P-450 Enzyme System; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D005978:Glutathione
Clin Gastroenterol Hepatol. 2007 Aug;5(8):917-20
17625975
Proc Natl Acad Sci U S A. 1984 Mar;81(5):1327-31
6424115
Arch Biochem Biophys. 1981 Jul;209(2):710-2
7294821
Int J Dermatol. 2009 Mar;48(3):326-8
19261029
Clin Cancer Res. 2007 Jun 15;13(12):3731-7
17575239
Clin Adv Hematol Oncol. 2008 Mar;6(3):191-199
18391918
Lung Cancer. 2004 Jul;45(1):93-104
15196739
Expert Opin Drug Metab Toxicol. 2006 Apr;2(2):261-72
16866612
Ann Pharmacother. 2009 Mar;43(3):542-5
19261961
Xenobiotica. 2009 Feb;39(2):99-112
19255936
Pediatrics. 2009 Feb;123(2):e297-304
19153164
Crit Rev Toxicol. 2002 Sep;32(5):391-411
12389869
Expert Opin Pharmacother. 2006 Feb;7(2):177-93
16433583
Chest. 2007 Sep;132(3):1042-4
17873198
Clin Lung Cancer. 2006 Dec;8 Suppl 1:S15-22
17239286
J Biol Chem. 1980 Jun 25;255(12):5578-85
7380828
Drug Metab Dispos. 2006 Mar;34(3):420-6
16381666
J Clin Oncol. 2008 Mar 1;26(7):1119-27
18309947
Transl Res. 2007 May;149(5):254-9
17466924
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71
16609030
Oncologist. 2005 Sep;10(8):579-89
16177282
J Clin Oncol. 2007 May 20;25(15):1960-6
17452677
Epilepsia. 2008 Dec;49(12):2087-91
18637831
Chem Res Toxicol. 2005 Apr;18(4):630-8
15833023
Chem Res Toxicol. 2007 Mar;20(3):344-69
17302443
Dermatology. 2008;216(3):247-9
18182820
BMC Cancer. 2007 Aug 05;7:150
17683587
Environ Health Perspect. 2006 Nov;114(11):1655-61
17107849
Expert Opin Drug Metab Toxicol. 2007 Jun;3(3):407-20
17539747
Drug Metab Dispos. 2009 Jun;37(6):1242-50
19282395
Drug Metab Rev. 2004 Oct;36(3-4):805-22
15554248
JOP. 2007 Jan 09;8(1):39-43
17228132