In vivo and in vitro characterization of chlorzoxazone metabolism and hepatic CYP2E1 levels in African green monkeys: Induction by chronic nicotine treatment

Anna M. Lee, Jiang Yue, Rachel F. Tyndale

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

CYP2E1 metabolizes compounds, including clinical drugs, organic solvents, and tobacco-specific carcinogens. Chlorzoxazone (CZN) is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased CZN clearance during smoking compared with nonsmoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo CZN area under the curve extrapolated to infinity (AUCinf) was 19.7 ± 4.5 μg x h/ml, t1/2 was 0.57 ± 0.07 h, and terminal disposition rate constant calculated from last three to four points on the log-linear end of the concentration versus time curve was 1.2 ± 0.2 /h. In vitro, the apparent Vmax was 3.48 ± 0.02 pmol/min/μg microsomal protein, and the Km was 95.4 ± 1.8 μM. Chronic nicotine treatment increased in vivo CZN disposition, as indicated by a 52% decrease in AUCinf (p < 0.01) and 52% decrease in Tmax (p < 0.05) compared with control-treated monkeys. The log metabolic ratios at 0.5, 1, 2, and 4 h significantly negatively correlated with CZN AUCinf (p = 0.01-0.0001). Monkey hepatic CYP2E1 levels significantly correlated with both in vivo AUCinf (p = 0.03) and in vitro (p = 0.004) CZN metabolism. Together, the data indicated that nicotine induction of in vivo CZN disposition is related to the rates of in vitro CZN metabolism and hepatic microsomal CYP2E1 protein levels. Nicotine is one component in cigarette smoke that can increase in vivo CZN metabolism via induction of hepatic CYP2E1 levels. Thus, nicotine exposure may affect the metabolism of CYP2E1 substrates such as acetaminophen, ethanol, and benzene.

Original languageEnglish (US)
Pages (from-to)1508-1515
Number of pages8
JournalDrug Metabolism and Disposition
Volume34
Issue number9
DOIs
StatePublished - Aug 31 2006

Fingerprint

Chlorzoxazone
Cercopithecus aethiops
Cytochrome P-450 CYP2E1
Nicotine
Metabolism
Liver
Area Under Curve
Haplorhini
Smoke
Tobacco Products
In Vitro Techniques
Tobacco
Acetaminophen
Benzene
Pharmaceutical Preparations
Carcinogens
Organic solvents
Rate constants

Cite this

In vivo and in vitro characterization of chlorzoxazone metabolism and hepatic CYP2E1 levels in African green monkeys : Induction by chronic nicotine treatment. / Lee, Anna M.; Yue, Jiang; Tyndale, Rachel F.

In: Drug Metabolism and Disposition, Vol. 34, No. 9, 31.08.2006, p. 1508-1515.

Research output: Contribution to journalArticle

@article{272d8b959c5043b98b501696b54b537a,
title = "In vivo and in vitro characterization of chlorzoxazone metabolism and hepatic CYP2E1 levels in African green monkeys: Induction by chronic nicotine treatment",
abstract = "CYP2E1 metabolizes compounds, including clinical drugs, organic solvents, and tobacco-specific carcinogens. Chlorzoxazone (CZN) is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased CZN clearance during smoking compared with nonsmoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo CZN area under the curve extrapolated to infinity (AUCinf) was 19.7 ± 4.5 μg x h/ml, t1/2 was 0.57 ± 0.07 h, and terminal disposition rate constant calculated from last three to four points on the log-linear end of the concentration versus time curve was 1.2 ± 0.2 /h. In vitro, the apparent Vmax was 3.48 ± 0.02 pmol/min/μg microsomal protein, and the Km was 95.4 ± 1.8 μM. Chronic nicotine treatment increased in vivo CZN disposition, as indicated by a 52{\%} decrease in AUCinf (p < 0.01) and 52{\%} decrease in Tmax (p < 0.05) compared with control-treated monkeys. The log metabolic ratios at 0.5, 1, 2, and 4 h significantly negatively correlated with CZN AUCinf (p = 0.01-0.0001). Monkey hepatic CYP2E1 levels significantly correlated with both in vivo AUCinf (p = 0.03) and in vitro (p = 0.004) CZN metabolism. Together, the data indicated that nicotine induction of in vivo CZN disposition is related to the rates of in vitro CZN metabolism and hepatic microsomal CYP2E1 protein levels. Nicotine is one component in cigarette smoke that can increase in vivo CZN metabolism via induction of hepatic CYP2E1 levels. Thus, nicotine exposure may affect the metabolism of CYP2E1 substrates such as acetaminophen, ethanol, and benzene.",
author = "Lee, {Anna M.} and Jiang Yue and Tyndale, {Rachel F.}",
year = "2006",
month = "8",
day = "31",
doi = "10.1124/dmd.106.010363",
language = "English (US)",
volume = "34",
pages = "1508--1515",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "9",

}

TY - JOUR

T1 - In vivo and in vitro characterization of chlorzoxazone metabolism and hepatic CYP2E1 levels in African green monkeys

T2 - Induction by chronic nicotine treatment

AU - Lee, Anna M.

AU - Yue, Jiang

AU - Tyndale, Rachel F.

PY - 2006/8/31

Y1 - 2006/8/31

N2 - CYP2E1 metabolizes compounds, including clinical drugs, organic solvents, and tobacco-specific carcinogens. Chlorzoxazone (CZN) is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased CZN clearance during smoking compared with nonsmoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo CZN area under the curve extrapolated to infinity (AUCinf) was 19.7 ± 4.5 μg x h/ml, t1/2 was 0.57 ± 0.07 h, and terminal disposition rate constant calculated from last three to four points on the log-linear end of the concentration versus time curve was 1.2 ± 0.2 /h. In vitro, the apparent Vmax was 3.48 ± 0.02 pmol/min/μg microsomal protein, and the Km was 95.4 ± 1.8 μM. Chronic nicotine treatment increased in vivo CZN disposition, as indicated by a 52% decrease in AUCinf (p < 0.01) and 52% decrease in Tmax (p < 0.05) compared with control-treated monkeys. The log metabolic ratios at 0.5, 1, 2, and 4 h significantly negatively correlated with CZN AUCinf (p = 0.01-0.0001). Monkey hepatic CYP2E1 levels significantly correlated with both in vivo AUCinf (p = 0.03) and in vitro (p = 0.004) CZN metabolism. Together, the data indicated that nicotine induction of in vivo CZN disposition is related to the rates of in vitro CZN metabolism and hepatic microsomal CYP2E1 protein levels. Nicotine is one component in cigarette smoke that can increase in vivo CZN metabolism via induction of hepatic CYP2E1 levels. Thus, nicotine exposure may affect the metabolism of CYP2E1 substrates such as acetaminophen, ethanol, and benzene.

AB - CYP2E1 metabolizes compounds, including clinical drugs, organic solvents, and tobacco-specific carcinogens. Chlorzoxazone (CZN) is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased CZN clearance during smoking compared with nonsmoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo CZN area under the curve extrapolated to infinity (AUCinf) was 19.7 ± 4.5 μg x h/ml, t1/2 was 0.57 ± 0.07 h, and terminal disposition rate constant calculated from last three to four points on the log-linear end of the concentration versus time curve was 1.2 ± 0.2 /h. In vitro, the apparent Vmax was 3.48 ± 0.02 pmol/min/μg microsomal protein, and the Km was 95.4 ± 1.8 μM. Chronic nicotine treatment increased in vivo CZN disposition, as indicated by a 52% decrease in AUCinf (p < 0.01) and 52% decrease in Tmax (p < 0.05) compared with control-treated monkeys. The log metabolic ratios at 0.5, 1, 2, and 4 h significantly negatively correlated with CZN AUCinf (p = 0.01-0.0001). Monkey hepatic CYP2E1 levels significantly correlated with both in vivo AUCinf (p = 0.03) and in vitro (p = 0.004) CZN metabolism. Together, the data indicated that nicotine induction of in vivo CZN disposition is related to the rates of in vitro CZN metabolism and hepatic microsomal CYP2E1 protein levels. Nicotine is one component in cigarette smoke that can increase in vivo CZN metabolism via induction of hepatic CYP2E1 levels. Thus, nicotine exposure may affect the metabolism of CYP2E1 substrates such as acetaminophen, ethanol, and benzene.

UR - http://www.scopus.com/inward/record.url?scp=33747839122&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33747839122&partnerID=8YFLogxK

U2 - 10.1124/dmd.106.010363

DO - 10.1124/dmd.106.010363

M3 - Article

C2 - 16763012

AN - SCOPUS:33747839122

VL - 34

SP - 1508

EP - 1515

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 9

ER -