Cytochromes P450 (CYPs) metabolize a vast array of xenobiotics, including many drugs and toxins. Induction or downregulation of the CYPs can have important consequences such as changes in drug efficacy and altered susceptibility to toxicity. Our study investigated the independent and combined effects of ethanol and nicotine on hepatic and/or brain levels of CYP2E1, CYP2B6 and CYP2A6 in African green monkeys. Monkeys were randomized into four groups (N = 10/group): an ethanol-only group, a nicotine-only group, an ethanol + nicotine group and a control (no drug) group. Ethanol (10% ethanol in sucrose solution) was voluntarily self-administered by the monkeys and nicotine was given as subcutaneous injections (0.5 mg/kg bid). Protein levels and/or in vitro activity were assessed in liver and brain tissue. Also, in vivo pharmacokinetics for chlorzoxazone (metabolized selectively by CYP2E1) and nicotine (metabolized primarily by CYP2A6 and to a lesser extent CYP2B6) were assessed. Hepatic CYP2E1 protein levels, in vitro hepatic CYP2E1 activity and in vivo chlorzoxazone metabolism were increased by ethanol and nicotine, alone and in combination. Hepatic CYP2B6 protein levels and in vitro hepatic CYP2B6 activity were increased by ethanol alone or combined ethanol and nicotine exposure, but were unaffected by nicotine alone. Hepatic CYP2A6 protein levels and in vitro hepatic CYP2A6 activity were decreased by nicotine alone or combined ethanol and nicotine exposure, but unaffected by ethanol alone. Chronic nicotine resulted in higher nicotine plasma levels achieved after nicotine administration, consistent with decreased CYP2A6 activity. Ethanol, alone or combined with nicotine, resulted in lower nicotine plasma levels, an effect that was not mediated by changes in CYP activity. Protein levels of CYP2E1 and CYP2B6 were induced in specific regions and cells in the brain as a result of ethanol self-administration, nicotine treatment and the combined exposure to both drugs. In summary, ethanol and nicotine can alter the expression and/or activity of several important CYP2 family enzymes in primate liver and/or brain.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/65659 |
| Date | 18 July 2014 |
| Creators | Ferguson, Charmaine |
| Contributors | Rachel, Tyndale |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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