Cytochrome P450 enzymes in the brain: emerging evidence of biological significance

Abstract

Cytochrome P450 (CYPs) enzymes are responsible for the metabolism of many exogenous and endogenous compounds. CYPs are abundant in the liver and are also expressed in many extra-hepatic tissues including the brain. Although the total CYP levels in the brain are much lower than in the liver, brain CYPs are concentrated near drug targets in specific regions and cell types, potentially having a considerable impact on local metabolism. Individual differences in brain CYP metabolism, due to inducers, inhibitors or genetic variation, can influence sensitivity and response to centrally acting drugs. Brain CYPs may also play a role in modulating brain activity, behavior, susceptibility to CNS diseases and treatment outcomes. This review highlights the recent progress that has been made in understanding the functional significance of CYPs in the brain.

Cytochrome P450–mediated drug metabolism in the brain

“…Brain CYPs are inducible, and the organ-and brain-region specificity of induction was found to be quite complex. 7,24,43,45,61 This, with the progressive discoveries that brain CYPs can metab olize endogenous neurochemicals, such as tyramine to dopamine by CYP2D6 62,63 and testosterone to 16α-hydroxytestosterone by CYP2B6, 10,64 lent credence to the idea that these enzymes may play a functional role in the brain in both endogenous and exogenous pathways.…”

“…6 Drug metabolism by CYPs takes place primarily in the liver, but CYP enzymes are also found in many other tissues, including brain. 7 It is predicted that local brain metabolism of centrally acting drugs at their site of action can influence their therapeutic efficacy independently of liver metabolism, and differences in brain levels of CYP enzymes can contribute to the observed interindividual variation in drug response. 7,8 There are many isoforms of CYPs, and these are classified into 18 families and 57 subfamilies based on their amino acid identity.…”

“…7 It is predicted that local brain metabolism of centrally acting drugs at their site of action can influence their therapeutic efficacy independently of liver metabolism, and differences in brain levels of CYP enzymes can contribute to the observed interindividual variation in drug response. 7,8 There are many isoforms of CYPs, and these are classified into 18 families and 57 subfamilies based on their amino acid identity. 9 Members of families 1, 2 and 3 primarily metabolize xenobiotics, such as drugs and environmentally derived compounds, and some endogenous substrates, whereas other vertebrate CYP family members primarily metabolize endogenous compounds.…”

“…9 Members of families 1, 2 and 3 primarily metabolize xenobiotics, such as drugs and environmentally derived compounds, and some endogenous substrates, whereas other vertebrate CYP family members primarily metabolize endogenous compounds. 5,7,[10][11][12] The CYP2 family metabolizes a large proportion of CNS-acting pharmacologics, such as antidepressants and antipsychotics; drugs of abuse, such as amphetamine and ethanol; and some endogenous neurochemicals, such as dopamine and serotonin. Some examples are presented in Tables 1 and 2.…”

The inhibitory activity of the extracts of popular medicinal herbs on CYP1A2, 2C9, 2C19 and 3A4 and the implications for herb-drug interaction

“…Its extracts inhibited the growth of cancer cells and induced apoptosis in an in vitro study (Bungu et al, 2006 (Paine et al, 2006). The CYP3A4 enzyme is the most important drug-metabolizing CYP accounting for about 40% of the total hepatic CYP (although the levels may vary 40-fold among individuals), and 50% of all CYP-mediated drug metabolism (Rendic, 2002;Ferguson and Tyndale, 2011;Singh et al, 2011). The inhibition of both intestinal and liver CYP3A4 has been shown to contribute to drugdrug interaction (Galetin et al, 2007).…”