The contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazine neuroleptics

Benzo(α)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

“…Both central and peripheral adrenoceptors are important therapeutic targets for a wide variety of drugs used in the treatment of hypertension, angina pectoris, congestive heart failure, cardiac arrhythmia, asthma, depression, prostatic hypertrophy, and glaucoma, among others (Virtanen, 1989;Lalchandani et al, 2004). Many of these drugs are also substrates for the cytochrome CYP1A2 (Fuhr and Rost, 1994;Yamazaki et al, 2001;Daniel et al, 2002;Llibre et al, 2002). This suggests that pharmacological manipulations of adrenoceptors and central noradrenergic systems, which may alter CYP1A2 and CYP1A1 expression, could contribute to various adverse effects including increased drug toxicity, drug therapy complications (Fuhr and Rost, 1994;Yamazaki et al, 2001;Daniel et al, 2002) and oncogenesis (IARC, 1983;Shimada et al, 1989;Kadlubar et al, 1990), among others.…”

“…Many of these drugs are also substrates for the cytochrome CYP1A2 (Fuhr and Rost, 1994;Yamazaki et al, 2001;Daniel et al, 2002;Llibre et al, 2002). This suggests that pharmacological manipulations of adrenoceptors and central noradrenergic systems, which may alter CYP1A2 and CYP1A1 expression, could contribute to various adverse effects including increased drug toxicity, drug therapy complications (Fuhr and Rost, 1994;Yamazaki et al, 2001;Daniel et al, 2002) and oncogenesis (IARC, 1983;Shimada et al, 1989;Kadlubar et al, 1990), among others. This is significant, mainly, for tobacco smokers and organisms exposed in heavily polluted with PAHs environment, such as the inhabitants of urban and industrial areas.…”

“…Cytochrome P450 isoform CYP1A2 is involved in the metabolism of a large spectrum of therapeutic drugs, including theophylline, lidocaine, imipramine, verapamil and phenothiazines, among others (Fuhr and Rost, 1994;Yamazaki et al, 2001;Daniel et al, 2002;Llibre et al, 2002). This suggests that concomitant administration of other drugs and ubiquitous foreign compounds, which induce or inhibit CYP1A2 activity, may lead to significant adverse reactions and complications in drug therapy (Fuhr and Rost, 1994).…”

“…Regarding their substrate specificity, CYP1A1 catalyzes mainly the metabolism of benzo(α)pyrene and related compounds that belong to PAHs, while CYP1A2 exhibits a high level of catalytic activity towards arylamines and potent pro-carcinogens derived from pyrolysates of amino acids and proteins (Gonzalez, 1989). In addition, CYP1A2, as above-mentioned, catalyzes the metabolism of various therapeutic drugs (Fuhr and Rost, 1994;Yamazaki et al, 2001;Daniel et al, 2002;Llibre et al, 2002).…”

Identification of phase-I metabolites and chronic toxicity study of the Kv1.3 blocker PAP-1 (5-(4-phenoxybutoxy)psoralen) in the rat

“…Effects of CYP isoenzymes on the metabolism of PAP-1 were also evaluated by using five selective inhibitors, including alpha-naphthoflavone for rat CYP1A1/2, quinidine for rat CYP2D6, diethyldithiocarbamate for rat CYP2E, sulfaphenazole for rat CYP2C9 and ketoconazole for rat CYP3A (Daniel et al, 2002; Martignoni and de Kanter, 2006; Erickson et al, 2007). Various concentrations (up to 100 μM) of inhibitors were preincubated with rat liver microsomes for 5 minutes at 37 °C, followed by the addition of PAP-1 (10 μM).…”