Other P450 Protein Modifying Inactivators

HPLC-analyses of heme extracts from PB-pretreated rabbit liver microsomes, incubated with or without PCP, identified PCP-modified heme fractions proposed to be iV-modified porphyrins, but the nature of these porphyrins was not established . It is therefore unclear whether heme modification or degradation was responsible for the loss of P450 activity or simply coincidental with it. However, a substantial discrepancy in the partition ratio obtained for PCP-mediated functional inactivation and that for heme loss suggested that this enzyme inactivation might also entail protein modification. 

Protein modification might indeed be primarily responsible for the PCP-mediated inactivation of CYP2B1 and -2B6, as no loss of heme chro-mophore in its ferric or CO-bound form was detected . Studies with CYP2B1- and CYP2B6-selective probes (7-ethoxycoumarin 

Other classes of compounds that inactivate human and rat liver microsomal P450 enzymes via protein modification are known. One such class is represented by the fiiranocoumarins, natural constituents of foods such as celery, parsley, figs, parsnips, and grapefruit juice . Among these compormds, the photoactive linear furanocoumarin, 8-MOP (methoxsalen) is a particularly potent P450 inactivator. Evidence that 

8-MOP was activated by P450 enzymes to an electrophilic product that bound covalently to the 

8-MOP is a potent inactivator of human liver C YP2A6 and rat liver CYP2B1, but also inactivates CYP2B2, -lA, -3A, and -2C11 -. Of all the furanocoumarins tested, 8-MOP was the most potent inactivator of CYP2B1 with a and 

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S.3.3.3 Other Inactivators That Modify the P450 Proteins... 

The oral contraceptive 17a-ethinylestradiol is a mechanism-based inactivator of P450 2B6 and modifies the (apo) protein [593,601], but the in vivo relevance of the inhibition has not been established. Inhibition by duloxetine has been described as being both reversible and time dependent [594]. Other P450 2B6 inhibitors include an acetylenic drag candidate [595], ticlopidine, clopidogrel [596, 597], phencyclidine [598], di-... 

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