Tags

Type your tag names separated by a space and hit enter

Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen.
Drug Metab Dispos. 2000 Dec; 28(12):1397-400.DM

Abstract

Acetaminophen (APAP), a widely used analgesic and antipyretic agent, can cause acute hepatic necrosis in both humans and experimental animals when consumed in large doses. It is generally accepted that N-acetyl-p-benzoquinone imine (NAPQI) is the toxic, reactive intermediate whose formation from APAP is mediated by cytochrome P450. Several forms of P450 in humans, including 2E1, 1A2, 2A6, 3A4, have been shown to catalyze the oxidation of APAP to NAPQI. We now present evidence which demonstrates that human cytochrome P450 2D6 (CYP2D6) is also involved in the bioactivation of APAP. The formation of NAPQI from APAP by cDNA-expressed CYP2D6 was examined. K(m) and V(max) values were 1.76 mM and 3.02 nmol/min/nmol of P450, respectively, such that the efficiency of CYP2D6 in the conversion of APAP to NAPQI is approximately one-third of that of CYP2E1. The contribution of CYP2D6 to the total formation of NAPQI from APAP (1 mM) in human liver was investigated using quinidine (1 microm) as a CYP2D6-specific inhibitor, and varied from 4.5 to 22.4% among 10 livers, with an average at 12.6%. The correlation between the contribution of CYP2D6 to NAPQI formation in human liver microsomes and the CYP2D6 activity probed by the O-demethylation of dextromethorphan was studied, and found to be strong (r(2) = 0.85), and significant (P <.0001). Our findings indicate that CYP2D6, one of the major P450 isoforms in humans and also one of the pharmacogenetically important isoforms, may contribute significantly to the formation of the cytotoxic metabolite NAPQI, especially in CYP2D6 ultra-rapid and extensive metabolizers and at toxic doses of APAP when plasma APAP concentrations reach 2 mM or more.

Authors+Show Affiliations

Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, 98195, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11095574

Citation

Dong, H, et al. "Involvement of Human Cytochrome P450 2D6 in the Bioactivation of Acetaminophen." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 28, no. 12, 2000, pp. 1397-400.
Dong H, Haining RL, Thummel KE, et al. Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug Metab Dispos. 2000;28(12):1397-400.
Dong, H., Haining, R. L., Thummel, K. E., Rettie, A. E., & Nelson, S. D. (2000). Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 28(12), 1397-400.
Dong H, et al. Involvement of Human Cytochrome P450 2D6 in the Bioactivation of Acetaminophen. Drug Metab Dispos. 2000;28(12):1397-400. PubMed PMID: 11095574.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. AU - Dong,H, AU - Haining,R L, AU - Thummel,K E, AU - Rettie,A E, AU - Nelson,S D, PY - 2000/11/30/pubmed PY - 2001/3/3/medline PY - 2000/11/30/entrez SP - 1397 EP - 400 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 28 IS - 12 N2 - Acetaminophen (APAP), a widely used analgesic and antipyretic agent, can cause acute hepatic necrosis in both humans and experimental animals when consumed in large doses. It is generally accepted that N-acetyl-p-benzoquinone imine (NAPQI) is the toxic, reactive intermediate whose formation from APAP is mediated by cytochrome P450. Several forms of P450 in humans, including 2E1, 1A2, 2A6, 3A4, have been shown to catalyze the oxidation of APAP to NAPQI. We now present evidence which demonstrates that human cytochrome P450 2D6 (CYP2D6) is also involved in the bioactivation of APAP. The formation of NAPQI from APAP by cDNA-expressed CYP2D6 was examined. K(m) and V(max) values were 1.76 mM and 3.02 nmol/min/nmol of P450, respectively, such that the efficiency of CYP2D6 in the conversion of APAP to NAPQI is approximately one-third of that of CYP2E1. The contribution of CYP2D6 to the total formation of NAPQI from APAP (1 mM) in human liver was investigated using quinidine (1 microm) as a CYP2D6-specific inhibitor, and varied from 4.5 to 22.4% among 10 livers, with an average at 12.6%. The correlation between the contribution of CYP2D6 to NAPQI formation in human liver microsomes and the CYP2D6 activity probed by the O-demethylation of dextromethorphan was studied, and found to be strong (r(2) = 0.85), and significant (P <.0001). Our findings indicate that CYP2D6, one of the major P450 isoforms in humans and also one of the pharmacogenetically important isoforms, may contribute significantly to the formation of the cytotoxic metabolite NAPQI, especially in CYP2D6 ultra-rapid and extensive metabolizers and at toxic doses of APAP when plasma APAP concentrations reach 2 mM or more. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/11095574/Involvement_of_human_cytochrome_P450_2D6_in_the_bioactivation_of_acetaminophen_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=11095574 DB - PRIME DP - Unbound Medicine ER -