Methoxyresorufin and benzyloxyresorufin: substrates preferentially metabolized by cytochromes P4501A2 AND 2B, respectively, in the rat and mouse

Nerurkar, Pratibha V.; Park, Sang S.; Thomas, Paul E.; Nims, Raymond W.; Lubet, Ronald A.

doi:10.1016/0006-2952(93)90504-p

Cited by 198 publications

(84 citation statements)

References 25 publications

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“…Increases were in the order (BROD >> EROD > MROD, T-6β-OH, T4-UDP-GT). MROD, EROD, and BROD activities are reported as being highly specific to CYP1A1, CYP1A2, and CYP2B of P450 (Nerurkar et al, 1993), respectively, while T-6β-OH activity is a highly specific to CYP3A (Arlotto et al, 1991). This suggests that while lindane most strongly induces CYP2B, it also induces a number of drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT.…”

Section: Figmentioning

confidence: 99%

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

et al. 2005

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-A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases in T3 and/or T4 in both sexes and generations at 300 ppm were presumed to be secondary changes associated with the induction of hepatic drug-metabolizing enzymes. Blood hormone analysis revealed no changes in sex hormones attributable to lindane in males or females. Hepatic drug-metabolizing enzyme activities were increased dose-dependently from 10 ppm in both sexes and generations, with the rise in BROD activity being the most prominent. There were also increases in MROD, EROD, T-6β-OH, and T4-UDP-GT activities (BROD >> EROD > MROD, T-6β-OH, T4-UDP-GT). This suggests that while lindane most strongly induces CYP2B, it also upregulates a number of other drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT. As for effects on reproductive function, lack of maternal behavior, including lactation and retrieval behavior, and consequent total litter loss were observed in F1 dams at 300 ppm. There were no effects of lindane on the estrous cycle, spermatogenesis, mating, fertility, pregnancy, or parturition. Neonatal toxicity was observed in bot...

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Section: Figmentioning

confidence: 99%

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

et al. 2005

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“…410 nm, em. 510 nm) formed in the case of BFCD, MFCD and EFCD activities (Nerurkar et al, 1993;Renwick et al, 2000;Donato et al, 2004). The incubation mixture consisted of 10 nmol of substrate, 200 nmol of NADPH and rat liver microsomes (0.1-0.3 mg protein) with test compounds in a final volume of 2 mL of 0.1 M K,Na-phosphate buffer (pH 7.4).…”

Section: Assay Of Cyp Activitiesmentioning

confidence: 99%

Cytochrome P450-inhibitory activity of parabens and phthalates used in consumer products

et al. 2016

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-The in vitro cytochrome P450 (CYP)-inhibitory effects of 11 parabens and 7 phthalates used in consumer products, as well as their hydrolytic metabolites, were investigated, using rat liver microsomes as an enzyme source. The effects on individual CYP isozymes were evaluated by assaying inhibition of activities towards specific substrates, i.e., ethoxyresorufin O-dealkylase (EROD), methoxyresorufin O-dealkylase (MROD), pentoxyresorufin O-dealkylase (PROD), 7-benzyloxy-4-trifluoromethylcoumarin dealkylase (BFCD), 7-methoxy-4-trifluoromethylcoumarin dealkylase (MFCD) and 7-ethoxy-4 -trifluoromethylcoumarin dealkylase (EFCD) activities. These activities were dose-dependently inhibited, most potently by medium-side-chain parabens (C6-9) and phthalates (C4-6), and less potently by shorterand longer-side-chain esters. The hydrolytic product of parabens, 4-hydroxybenzoic acid, was not inhibitory, while those of phthalates, phthalic acid monoesters, showed lower inhibitory activity than the parent phthalates. Parabens showed relatively potent inhibition of MFCD activity, considered to be mainly due to CYP2C, and phthalates showed relatively potent inhibition of PROD activity, considered to be mainly due to CYP2B.

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“…Homogenate was initially centrifuged at 14000g for 20 min in a cold centrifuge (Remi) and supernatant was then further centrifuged at 10, 5000 g for 1 h in an ultracentrifuge (Sorvall). The microsomes obtained from liver homogenate were washed and resuspended in cold phosphate buffer (pH 7.4, 0.1 M) and used for determination of the effect of TEO on the dealkylation of methoxy resorufin by 7-methoxyresorufin-O-demethylase (MROD), CYPIA2, pentoxy resorufin by 7-pentoxyresorufin-O-depentylase (PROD), CYP2B1/2 and ethoxy resorufin by 7-ethoxyresorufin-O-deethylase (EROD), CYP1A1 (Pohl and Fouts, 1980;Nerurkar et al, 1993).…”

Section: Effect Of Teo On the Inhibition Of Various Isoforms Of Cytocmentioning

confidence: 99%

Chemopreventive Activity of Turmeric Essential Oil and Possible Mechanisms of Action

Liju¹,

Jeena²,

Kuttan³

2014

Asian Pacific Journal of Cancer Prevention

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Asian Pac J Cancer Prev, 15 (16), 6575-6580 IntroductionMany human cancers are caused by chemical carcinogens, such as polycyclic aromatic hydrocarbons, heterocyclic amines, aromatic amines etc present in our environment. Continued exposure of these substances to human cells leads to genomic instability, including repair deficiency and accumulation of genetic alteration (Ames, 1983). Mutation is a major factor in carcinogenesis and incidence of cancer may be reduced by decreasing the rate of mutations induced by various chemical mutagens. Many carcinogens are activated through Phase I (cytochrome p450) enzymes present in endoplasmic reticulum of the liver cells. Induction of Phase II detoxification enzymes, such as glutathione S-transferase and UDP-glucuronyl transferase, is another mechanisms of protection against carcinogenesis (Piengchai et al., 2011). Modulating these enzymes may reduce cancer incidence.Spices which are widely used as food ingredient exhibits different pharmacological properties. Essential oils from spices are volatile compounds produced as secondary metabolites. The essential oil from Curcuma longa rhizome is a complex mixture obtained by steam distillation. A total number of 12 components of the essential oil are identified by GC-MS analysis and the principal compounds include ar-turmerone (61%), Department of Biochemistry, Amala Cancer Research Centre, Kerala, India *For correspondence: amalacancerresearch@gmail. com, amalaresearch@hotmail.com AbstractThis study aimed to evaluate the antimutagenic and anticarcinogenic activity of turmeric essential oil as well as to establish biochemical mechanisms of action. Antimutagenicity testing was accomplished using strains and known mutagens with and without microsomal activation. Anticarcinogenic activity was assessed by topical application of 7, 12 -dimethylbenz[a]anthracene (DMBA) as initiator and 1% croton oil as promoter for the induction of skin papillomas in mice. Inhibition of p450 enzymes by TEO was studied using various resorufins and aminopyrene as substrate. Turmeric essential oil (TEO) showed significant antimutagenic activity (p<0.001) against direct acting mutagens such as sodium azide (NaN 3 ), 4-nitro-O-phenylenediamine (NPD) and N-methyl-N-nitro N'nitrosoguanine (MNNG). TEO was found to have significant antimutagenic effect (>90%) against mutagen needing metabolic activation such as 2-acetamidoflourene (2-AAF). The study also revealed that TEO significantly inhibited (p<0.001) the mutagenicity induced by tobacco extract to Salmonella TA 102 strain. DMBA and croton oil induced papilloma development in mice was found to be delayed and prevented significantly by TEO application. Moreover TEO significantly (P<0.001) inhibited isoforms of cytochrome p450 (CYP1A1, CYP1A2, CYP2B1/2, CYP2A, CYP2B and CYP3A) enzymes in vitro, which are involved in the activation of carcinogens. Results indicated that TEO is antimutagenic and anticarcinogenic and inhibition of enzymes (p450) involved in the activation of carcinogen is one of its mecha...

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Methoxyresorufin and benzyloxyresorufin: substrates preferentially metabolized by cytochromes P4501A2 AND 2B, respectively, in the rat and mouse

Cited by 198 publications

References 25 publications

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

Cytochrome P450-inhibitory activity of parabens and phthalates used in consumer products

Chemopreventive Activity of Turmeric Essential Oil and Possible Mechanisms of Action

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