Chronic nicotine treatment can induce human CYP2D6 expression: isit anot inducible enzyme yet?

Cytochromes P450 (CYPS) are a superfamily of heme-containing mono-oxygenases that metabolise many xenobiotics, including drugs, carcinogens and toxicants, as well as endogenous compounds such as catecholamines, fatty acids and neurotransmitters. Many of the drug metabolising CYP450 enzymes belong to the CYP2 family, which is highly polymorphic. Genetic varíation In these enzymes can result in reduced or Increased metabolism of drugs, and can affect drugs interaction, drugs efficacy and drugs toxicity. Genetic polymorphism have also been associated with addictlon and neurological diseases (Miskys and Tyndale, 2004). CYP2D6, a representative member of C'íPZ family, is a genetically polymorphic enzyme (http://www.cypalleles.kl.se/cyp2d6.htm) involved in the metabollsm of endogenous (e.9. dopamine) and exogenous substrates. It metabollses approximately 25olo of all clinically used drugs including analgeslcs (e.9, codeine), neuroleptlcs (e.9. clozapine), trlcyclic antidepressants (e.9. imipramine), antidepressants (e.S. fluoxitine and citalopram) and several recreational drugs of abuse (e.9. ecstasy). Beside of its typical expression In the liver, CYP2D6 is widely expressed in several extrahepatic tissues, In particular in dlfferent regions of the brain, such as the hippocampus, thalamus, hypothalamus, substantia nigra, cerebellum and the cortex. It is worth noting that not only the CYP2D6 mRNA and protein, but also its corresponding enzymatlc activity have been detected in the human brain (Kircheiner et al. 2010). Besides humans, CYP2D6 has also been found in dog, rat and monkey brain, where it readlly metabolise CYP2D6 probe drugs (e.9. dextromethorphan) thus suggesting that the enzyme is functional. Although CYP2D6 is essential a not inducible enzyme in the liver, some studies reported that human smokers have hlgher levels of brain CYP2D6 but unchanged level of hepatic CYP2D6, compared to non-smokers. ln two different studies, it has been found that chronic nicotine treatment can induce brain CYP2D6 in rodents and monkeys. Thís induction involved increased protein level with no change in mRNA level, thus indicating that the CYP2D6 increase in the brain, upon nicotine treatment, is probably due to post-transcriptional mechanisms, such as increased translation efficiency or protein stabilisation. If brain CYP2D6 is induced by nicotine, this could affect brain metabolism in a large portion of population, not only in smokers, but also those exposed to environmental tobacco smoke and those undergoing nicotine replacement therapy (Yue et al. 2006; Mann et al. 2008). On the basis of these findings we address our attention on the effects of nicotine treatment in a human cellular model that permanently express CYP2D6. Due to the low level of CYP2D6 in brain with respect to liver and mainly due to the low expression of this enzyme in in vitro cells culture, the human neuroblastoma SH-SYSY and the human hepatocarcinoma HepG2 cell lines have been steadily transfected with CYP2D6 cDNA. With these cellular models we are now attemptlng to understand the effects of chronic nicotine treatment on the expression and metabolic activity of CYP2D6 in order to characterise the mechanisms underlying the hypothesized posttranscriptional or post-translational fine regulatlon of CYP2D6. Kirchheiner et al. (2010). Mol. Psychiatry. 16 (3), 333-341. Mfskys and Tyndale. (2004). Drug metabolism reviews. 36 (2),313-333. Mann et al. (2006). Neuropharmacology. 55, 1147-1155. Yue et al. J. Psychiatry Neurosci. 33 (1), 54-63.