Unique cytochromes P450 in human brain: implication in disease pathogenesis.

Cytochromes P450 is a family of heme proteins that metabolize xenobiotics including drugs. Unique human brain cytochrome P450 enzymes metabolize xenobiotics including drugs to active/inactive metabolites through biotransformation pathways that are different from the well-characterized ones in liver. We have identified an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 in human brain but not in liver or kidney from the same individual. Genotyping revealed the presence of the frame-shift mutation 138delT only in those subjects who expressed the brain variant CYP2D7, which metabolizes codeine exclusively to morphine unlike hepatic CYP2D6 that metabolizes codeine to nor codeine and morphine. CYP1A1 bioactivates polycyclic aromatic hydrocarbons to reactive DNA binding metabolites and initiates carcinogenesis. We have identified a unique splice variant of CYP1A1 having deletion of 87 bp of exon 6 which is present in human brain but not in liver of the same individual. We present evidence for the existence of biotransformation pathways in human brain that are dissimilar from known pathways in liver. Identification and characterization of novel CNS-specific P450 enzymes generated by alternate splicing of known genes or as yet unidentified genes may help predict consequences of exposure to xenobiotics including pesticides in the brain.

Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite.

Cytochrome P450 (P450) is a superfamily of enzymes which mediates metabolism of xenobiotics including drugs. Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and alpha-hydroxy alprazolam (alpha-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of alpha-OHALP formed in brain was higher than liver. This biotransformation was mediated by a P450 isoform belonging to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and human brain. The formation of larger amounts of alpha-OHALP in neurons points to local modulation of pharmacological activity in brain, at the site of action of the anti-anxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily cleared through blood-CSF barrier, alpha-OHALP would potentially have a longer half-life in brain.

Malignant melanoma of the choroid with vitiligo.

An unusual case of an Asian patient with malignant melanoma of the choroid with vitiligo is reported. Other uncommon features of this case are metastasis to an extrahepatic site without liver metastasis and infiltration of the optic nerve.