Effects Of Cytochrome P450 Induction Research Articles

Effects of CYP Induction by Rifampicin on Tamoxifen Exposure

Tamoxifen undergoes biotransformation into several metabolites, including endoxifen. Differences in metabolism contribute to the interindividual variability in endoxifen concentrations, potentially affecting treatment efficacy. We evaluated the effects of cytochrome P450 (CYP) induction by rifampicin on the exposure levels of tamoxifen and its metabolites and found that coadministration of rifampicin resulted in markedly reduced (up to 86%, P ≤ 0.040) concentrations of tamoxifen and its metabolites. Given the extensive metabolism undergone by tamoxifen, several factors may have contributed to this effect. Similar drug-drug interactions may exist between tamoxifen and other strong CYP inducers.

N-Nitrosodiethylamine genotoxicity in primary rat hepatocytes: Effects of cytochrome P450 induction by phenobarbital

Primary hepatocytes are widely used in investigating drug metabolism and its toxicological effects. N-Nitrosodiethylamine (NDEA)-induced genotoxicity and cytotoxicity was used in primary cultures of female rat hepatocytes in the presence of phenobarbital (PB). PB pre-treatment (1mM) increased the number of necrotic (2-fold) and apoptotic cells (4-fold) after NDEA treatment (0.21–105μg/mL). The mitotic indices and the number of micronucleated cells decreased, thus suggesting cytotoxicity. An increased number of chromosomal aberrations were observed after pre-treatment with PB. NDEA-treatment (0.21–21μg/mL) induced expression of the CYP2B1 and CYP2B2 mRNA and PB treatment alone induced ∼6-fold and ∼2-fold increases of CYP2B1 and CYP2B2 mRNA, respectively. NDEA treatment following PB exposure increased CYP2B1 mRNA expression under all tested concentrations and also increased CYP2B2 expression at 21 and 105μg/mL. Our data suggest that the alteration of CYP2B1/2 expression by PB increased the cytotoxicity and genotoxicity of NDEA leading to the final genotoxic metabolite.

Sublethal exposure to crude oil during embryonic development alters cardiac morphology and reduces aerobic capacity in adult fish

Exposure to high concentrations of crude oil produces a lethal syndrome of heart failure in fish embryos. Mortality is caused by cardiotoxic polycyclic aromatic hydrocarbons (PAHs), ubiquitous components of petroleum. Here, we show that transient embryonic exposure to very low concentrations of oil causes toxicity that is sublethal, delayed, and not counteracted by the protective effects of cytochrome P450 induction. Nearly a year after embryonic oil exposure, adult zebrafish showed subtle changes in heart shape and a significant reduction in swimming performance, indicative of reduced cardiac output. These delayed physiological impacts on cardiovascular performance at later life stages provide a potential mechanism linking reduced individual survival to population-level ecosystem responses of fish species to chronic, low-level oil pollution.

Nitroreduction of 2,4-dinitrotoluene [formula omitted] by cytochrome P-450 induced H4IIE cells

Conditions have been established for H4IIE rat hepatoma cell cultures in which effects of cytochrome P-450 induction on the metabolism of a munitions wastestream pollutant can be studied. Under these conditions, the polychlorinated hydrocarbon 2,3,4,7,8-pentachlorodibenzfuran (PCDBF) induced cytochrome P-450 (1A1) aryl hydrocarbon hydroxylase (AHH) activity over a wide range of concentrations without significant cytotoxic effects. The munition pollutant 2,4-dinitrotoluene (2,4-DNT) did not induce AHH activity itself, but its metabolism was considerably altered when applied to PCDBF induced cultures. Production of amino nitrotoluene isomers was greatly enhanced in induced cultures as compared to uninduced controls, as was the conversion of radiolabeled 2,4-DNT to relatively more polar metabolites. To some extent, the results with H4IIE cells parallel those reported for animals exposed to 2,4-DNT after induction of cytochrome P-450 AHH activity. The preliminary findings suggest that with further development and validation, H4IIE cultures could be of use in characterizing metabolites that result from exposure to chemical mixtures involving a P-450 (1A1) inducer.

σRecognition sites in brain and peripheral tissues Characterization and effects of cytochrome P450 inhibitors

Binding to σ sites in subcellular fractions of brain and in crude homogenates from peripheral tissues of the guinea pig was characterized with the [ 3H]ligands (+)pentazocine and di(2-tolyl)guanidine (DTG). The inhibitory effects of representative σ compounds and cytochrome P450 inhibitors were evaluated in guinea pig tissues, and the effects of cytochrome P450 induction σ binding in the rat were investigated. For both ligands, the majority of sites were localized to the microsomal fractions. The K D values for [ 3H](+)pentazocine- or [ 3H]DTG-labeled by sites in guinea pig liver and testes were 2-fold lower than those in brain and heart. The number of sites labeled by [ 3H](+)pentazocine varied, with an order of liver>testes>brain>heart. In contrast, the B MAX values for [ 3H]DTG-defined σ sites were greatest in testes, followed by liver, brain and heart. The rank order of potency for representative σ and P450 compounds was similar in brain, liver and testes for both [ 3H]ligands, and the potency of selective compounds to displace σ binding in guinea pig liver failed to correlate with their abilities to inhibit cytochrome P450IID1 activity in human liver. Following induction of cytochrome P450IIB1 with phenobarbital or cytochrome P450IA1 with β-naphthoflavone, neither the affinity nor the number of σ sites was altered in rat brain or liver. These results suggest that σ sites in the periphery are similar to those in the brain, and that the σ binding site is not identical with cytochrome P450IIB1, P450IA1 or P450IID1.

Differential effects of cytochrome P-450 induction on ligand binding to σ receptors

The identity of the σ receptor as a form of cytochrome P-450 was investigated in rats treated with 3-methylcholanthrene or phenobarbital. The density of [ 3H]N,N′-di(o-toly)guanidine (DTG) binding to σ 2 receptors in hepatic subcellular fractions increased following both treatments, while [ 3H](+)-pentazocine binding to σ 1 receptors was unchanged. Furthermore, proadifen and piperonyl butoxide inhibited [ 3H](+)-pentazocine and [ 3H]DTG binding with low potency. The low affinity of cytochrome P-450 inhibitors for σ receptors, the similar degree of enhancement of [ 3H]DTG binding by agents with disparate cytochrome P-450 induction profiles and the lack of change in [ 3H](+)-pentazocine binding are inconsistent with the identity of the σ receptor as a cytochrome P-450.