Cytochrome P450-catalyzed pathways in human brain: metabolism meets pharmacology or old drugs with new mechanism of action?

The true importance of cytochrome P450 enzymes, not just in drug metabolism but also in pharmacology, is only beginning to be appreciated. Though originally discovered through their role in the biotransformation of xenobiotics, the P450 enzyme super family is ubiquitous in nature and necessarily evolved around endogenous pathways. The extent of tissue- and cell-specific expression of individual P450 isoforms has led many investigators to hypothesize localized roles in endogenous biochemical pathways for isoforms traditionally thought of as drug-metabolizing. In some cases, direct evidence from humanized transgenic animal models can confirm the degree to which such enzymes modulate endogenous pathways. However, overlapping P450 substrate specificities may mask genetic or biochemical deficiencies, such that many of these reactions appear nonessential. Nonetheless, the drug-induced alteration of local biochemical concentrations in extrahepatic tissues due to metabolism by and inhibition of P450 isoforms has tremendous potential for introducing unexpected pharmacological effects. Nowhere is this truer than in the CNS. On the other hand, if we can harness the power of in silico modeling to create highly specific inhibitors of identified brain isoforms, a novel avenue for drug design using P450 as drug targets may be at hand. This article highlights some notable examples in which the catalytic state of specific P450 isoforms involved in endogenous biochemical reaction pathways are influenced by pharmacological agents. The implications of inhibition of P450-catalzyed oxidation steps that are known or speculated to influence arachadonic acid, cholesterol, and catecholamine neurotransmitters pathways in human brain will be considered.