Disease relevance of Didrex

• CYP3A9 cDNA was expressed in E. coli and the expressed P450 3A9 is active in the demethylation of erythromycin as well as benzphetamine [1].
• In the reconstituted system, hepatoma P-450MCI catalyzed 3-hydroxylation of benzo[a]pyrene and O-deethylation of 7-ethoxycoumarin, but showed low activities for N-demethylation of benzphetamine and aminopyrine, O-demethylation of p-nitroanisole, and p-hydroxylation of aniline [2].
• When 1,1-di(p-chlorophenyl)-2,2-dichloroethylene (DDE) (100 mg/kg body weight) was injected into rats, the benzphetamine N-demethylation and 7-ethoxycoumarin O-deethylation activities of liver microsomes increased by 7-fold and 3-fold, respectively, at 7 days after the injection, whereas the benzo(a)pyrene 3-hydroxylation activity did not increase [3].
• Additional evidence for thiram-induced liver toxicity is provided by the observation that there was approximately 50% inhibition of the activity of hepatic microsomal benzphetamine N-demethylase with a concomitant decrease in the concentration of cytochrome P-450, an important component of the mixed-function oxidase system [4].

High impact information on Didrex

• Monooxygenase activities (pmol product/min/protein) in the bladder microsomal fraction were observed for benzphetamine N-demethylation (290), 7-ethoxyresorufin O-deethylation (29), 7-ethoxycoumarin O-deethylation (28), benzo(a)pyrene hydroxylation (10), and 2-aminofluorene hydroxylation (1400) [5].
• In vitro addition of (+)-catechin gave rise to a dose-dependent inhibition of the cytochrome P-450-dependent benzphetamine N-demethylase and ethoxyresorufin O-deethylase activities [6].
• The protein expressed in COS-7 cells using the cDNA in an expression vector, pKCRH2, shows benzphetamine N-demethylase activity and gives a band identical with that of P-450ib in its mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis [7].
• Cytochrome P-450 LM2 reduction was measured at a series of NADPH concentrations in the absence of substrate and in the presence of 1 mM benzphetamine [8].
• When examined either in the absence or presence of benzphetamine, the rate constant and fraction of LM2 reduced in the fast phase were decreased as the NADPH concentration was decreased [8].

Biological context of Didrex

• The rate of electron transfer from b5 to oxyferrous P-450, derived from the kinetics of reoxidation of either b5 or P-450, was increased from 2.5 s-1 to about 4 to 7 s-1 in the presence of 1 mM benzphetamine [9].
• The activity, however, was restored to preparations from both PB-induced and 3-MC-induced mitochondrial enzymes (AFB1 activation, ethylmorphine, and benzphetamine deamination and BaP metabolism) by addition of purified rat liver cytochrome P-450 reductase, and beef adrenodoxin and adrenodoxin reductase [10].
• Little or no sex difference in metabolism was observed with benzo[a]pyrene or benzphetamine as substrates [11].
• Orientation of substrates within the active site of the BBT-inactivated enzyme may be affected such that the more flexible benzphetamine can be metabolized, whereas metabolism of rigid, planar molecules such as EFC and testosterone is hindered [12].
• A kinetic study comparing the light-reversal properties of carbon monoxide inhibition of ethylmorphine, benzphetamine, and 7-ethoxycoumarin dealkylation with those of hydroxylation of 17-hydroxyprogesterone and testosterone [13].

Anatomical context of Didrex

• Benzyl hydrodisulfide decreased enzymatic activity toward benzphetamine when incubated with hepatic microsomes prior to the assay for monooxygenase activity [14].
• The antibody exerted different effects in inhibiting d-benzphetamine N-demethylase and benzo[a]pyrene hydroxylase activities as compared to NADPH-cytochrome c reductase activity in human liver microsomes [15].
• In untreated animals, CYP2D16 protein and messenger RNA (mRNA) expression as well as xenobiotic-metabolizing activities (bufuralol 1'-hydroxylase, benzphetamine N-demethylase, and benzo(a)pyrene hydroxylase) were far greater in the inner (zona reticularis) than the outer (zona fasciculata plus zona glomerulosa) zones of the cortex [16].
• In addition, in vitro administration of 4-ethyl DDC and TTMS caused mechanism-based inactivation of benzphetamine N-demethylase activity in microsomes from phenobarbital- and glutethimide-treated chick embryos, showing that the chick embryo hepatic P450 2H isozyme is a target for mechanism-based inactivation [17].
• The individual congeners identified were examined for accumulation in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase, and DT-diaphorase in rats, and gravimetric changes of the thymus and liver in rats [18].

Associations of Didrex with other chemical compounds

• Under the same conditions, microsomal activities of hydroxylation of benzo[a]pyrene and N-demethylation of benzphetamine were significantly induced by the pretreatments with 3-methylcholanthrene and phenobarbital, respectively [19].
• When added to the reconstituted system, the cytochrome P-448 antibody inhibits purified rat cytochrome P-448- and P-450-supported N-demethylation of benzphetamine, O-deethylation of ethoxycoumarin, hydroxylation of benzo[a]pyrene, and the hydroxylation of testosterone at the 6beta, 7alpha, and 16alpha positions [20].
• The oxidation-reduction potential is unaffected by the presence of phosphatidylcholine or benzphetamine, a typical substrate [21].
• CYP2C25, CYP2C26, and CYP2C27 proteins expressed in Saccharomyces cerevisiae catalyzed the hydroxylation of tolbutamide and the N-demethylation of aminopyrine and benzphetamine [22].
• Catalytic activities toward benzphetamine and 7-ethoxycoumarin of 11 distal mutants, 9 proximal mutants, and 3 aromatic mutants of rat liver cytochrome P-450d were studied [23].

Gene context of Didrex

• In liver, methanol extract at 2 g/kg caused 47%, 7-, 8-, 4-fold, 81% and 26% increases of benzo(a)pyrene hydroxylation (AHH), EROD, 7-methoxyresorufin O-demethylation (MROD), 7-ethoxycoumarin O-deethylation (ECOD), benzphetamine N-demethylation, and N-nitrosodimethylamine N-demethylation activities, respectively [24].
• Both Cyp3a (7.4-fold) and Cyp2b (1.8-fold) type enzymes were shown by western immunoblot analysis to be induced by dexamethasone, the latter correlating more closely with increased SR 4233 reductase activity and also with the 2-fold induction of benzphetamine N-demethylase, a Cyp2b-type enzyme [25].
• SR 4233 itself inhibited benzphetamine N-demethylase, which is catalysed by Cyp2b-type enzymes but not erythromycin N-demethylase which is catalysed by Cyp3a-type isoforms [25].
• Anti-CYP3A4 antibody had no effect on that activity in fetal or in adult liver microsomes, whereas a monoclonal antibody 1-68-11 (generated against rat CYP2C11) slightly inhibited benzphetamine N-demethylase activity in adult liver [26].
• The role of cytochrome P450 3A (CYP3A) isoform(s) in oxidative metabolism of testosterone and benzphetamine in human adult and fetal liver [26].

Analytical, diagnostic and therapeutic context of Didrex

• Microsomal benzphetamine N-demethylation was decreased by ETOH, INH and BF administration and was only modestly enhanced after treatment with PB [27].
• Hepatic cytochrome P450 (CYP) content, ethoxyresorufin O-deethylase activities, and levels of metabolites arising from phase I metabolism were doubled after repeat oral administration of DDS, but benzphetamine N-demethylase activity was unchanged [28].
• Benzphetamine metabolite analysis by electrospray ionization-mass spectrometry showed that the BBT-modified enzyme had a slightly greater propensity towards aromatic hydroxylation together with reduced levels of N-demethylation and little change in the N-debenzylation of benzphetamine [12].
• Cytochrome P-450 content and the in vitro rate of metabolism of benzphetamine and zoxazolamine were maximally depressed 8-24 hr after a single intraperitoneal injection of 1.5 micrograms of interferon per mouse; at this time the interferons were no longer detectable in serum [29].
• Development of a method for the quantitation of benzphetamine metabolites in human urine by high-performance liquid chromatography [30].

References