Back to the Top
Dear List members,
Has anyone out there got any references (or personal knowledge) about
of paracetamol via the CYP2E1 - I'm particularly interested to know
maturation of this system has been documented?
Dr. Tom G. Hansen,
Department of Anaesthesia & Intensive Care,
Odense University Hospital,
DK-5000 Odense C,
Back to the Top
From a recent abstract, it appears that CYP2E1 is the isoenzyme
responsible for the formation of the toxic metabolite of acetaminophen
or paracetamol (NAPQI) which causes hepatic necrosis from overdoses.
Here is the abstract.
Mike Leibold, PharmD, RPh
Chen W. Koenigs LL. Thompson SJ. Peter RM. Rettie AE. Trager WF. Nelson
Department of Medicinal Chemistry, University of Washington, Seattle,
Washington 98195, USA.
Oxidation of acetaminophen to its toxic quinone imine and
nontoxic catechol metabolites by baculovirus-expressed and purified human
cytochromes P450 2E1 and 2A6.
Chemical Research in Toxicology. 11(4):295-301, 1998 Apr.
Acetaminophen (APAP), a widely used analgesic and
antipyretic agent, is bioactivated by cytochromes P450 to
cause severe hepatotoxicity. APAP is oxidized by two pathways to form a toxic
intermediate, N-acetyl-p-benzoquinone imine (NAPQI), and a nontoxic catechol
metabolite, 3-hydroxy-APAP (3-OH-APAP). We investigated the role of P450 2E1
and 2A6 in APAP oxidation by using baculovirus-expressed and highly purified
forms of human P450 2E1 and 2A6. An electrochemical HPLC assay was developed
to quantify both oxidative metabolites simultaneously. For the first time, it
was demonstrated that human P450 2E1 selectively oxidized APAP to NAPQI
(assayed as its glutathione conjugate, GS-APAP), whereas human P450 2A6
selectively oxidized APAP to 3-OH-APAP. At 1 mM APAP, the relative ratio for
the formation of GS-APAP vs 3-OH-APAP with human P450 2E1 was approximately
6:1, whereas the ratio with human P450 2A6 was 1:3. Apparent Km and Vmax
values for the formation of GS-APAP by human P450 2E1 were 1.3 mM and 6.9
nmol/min/nmol of P450, respectively, whereas they were 4.6 mM and 7.9
nmol/min/nmol of P450 for P450 2A6. Apparent Km and Vmax values for the
formation of 3-OH-APAP by human P450 2E1 were 4.0 mM and 2.5 nmol/min/nmol of
P450, respectively, whereas they were 2.2 mM and 14.2 nmol/min/nmol of P450,
respectively, for P450 2A6. Thus, although at toxic doses of APAP P450 2E1 is
the more efficient catalyst for the formation of the toxic metabolite NAPQI,
P450 2A6 also can contribute significantly to NAPQI production.
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (email@example.com)