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Vol. 25, Issue 12, 1429-1435, 1997
The Agouron Institute (J.L.R., E.D.S., M.R.W., S.P.C.) and
Department of Internal Medicine, Division of Gastroenterology (S.A.,
D.E.J.), and
Department of Biochemistry (J.L.O.), University of New
Mexico School of Medicine
Cytochrome P450 (CYP) 2E1 is implicated in a variety of chemically
initiated hepatotoxicities, including alcoholic liver disease. These
pathological conditions arise from increased production of reactive
intermediates caused by elevated enzyme concentrations. Thus, the
ability to detect enhanced CYP2E1 levels would aid in identifying
individuals at high risk for xenobiotic-promoted liver injury. With
this in mind, the present investigation assessed in vivo
chlorzoxazone metabolism and compared pharmacokinetic parameters with
CYP2E1 expression in blood. Twenty-two subjects were recruited and
divided into two groups, control subjects and alcohol abusers, based on
responses to two screening questionnaires. Those individuals with
higher survey scores, i.e. those who consumed alcohol more
frequently, exhibited higher rates of chlorzoxazone metabolism. Indeed,
a correlation (r = 0.66, p < 0.01)
was obtained when scores were compared with the pharmacokinetic
parameter AUC for chlorzoxazone. Lymphocyte microsomes isolated from
blood samples obtained from these same individuals were subjected to
immunoblot analyses to detect CYP2E1 levels. That lymphocytes contained
CYP2E1 was confirmed by reverse transcription-polymerase chain reaction and sequence analysis of the cDNA. Quantification of immunoreactive bands revealed that levels of this P450 were 2.3-fold higher in alcoholics than in control subjects. This increase in lymphocyte CYP2E1
content in alcoholic subjects coincided with a 2.1-fold increase in
chlorzoxazone clearance and a 2-fold decrease in the AUC for
chlorzoxazone. Importantly, a correlation (r = 0.62, p < 0.01) was observed between CYP2E1 content in
lymphocytes and chlorzoxazone clearance rates. Thus, monitoring
lymphocyte CYP2E1 expression may provide a substitute for estimating
hepatic activity of this P450.
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