Different modes of inhibition of mouse Cyp2a5 and rat CYP2A3 by the food-derived 8-methoxypsoralen

Visoni, S.B.C.; Meireles, N.; Monteiro, Luiz Antonio Cavalcanti; Rossini, Ana; Pinto, Luís Felipe Ribeiro

doi:10.1016/j.fct.2007.12.001

Cited by 14 publications

(18 citation statements)

References 30 publications

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“…The ability of 8-MOP to act as a mechanism-based inhibitor of CYP2A enzymes has been well documented (Koenigs et al, 1997;von Weymarn et al, 2005); 8-MOP was also found to inhibit mouse CYP2A5 through additional (competitive and noncompetitive) mechanisms (Visoni et al, 2008). However, the specificity of inhibition of CYP2A enzymes by 8-MOP is not absolute, particularly at high 8-MOP concentration or doses; e.g., 8-MOP inhibited mouse hepatic microsomal metabolism of carbon tetrachloride, a CYP2E1 substrate, and caffeine, a CYP1A2 substrate, both in vitro and in vivo (Labbe et al, 1987;Apseloff et al, 1991).…”

Section: -Mop Dosementioning

confidence: 99%

“…The effects of 8-MOP on NNK bioactivation were further investigated in vitro, using lung and liver microsomes from Cyp2a5-null mice, and a 8-MOP preincubation scheme to mimic the pretreatment paradigm used in vivo, given the potential role of 8-MOP as mechanism-based, competitive, and noncompetitive P450 inhibitors (Visoni et al, 2008). A pilot study (data not shown) indicated that 20-min preincubation with 8-MOP led to maximal inhibition of the activities toward NNK in either lung or liver microsomes from Cyp2a5-null mice.…”

Section: Effects Of 8-mop On the Clearance And Bioactivation Of Nnkmentioning

confidence: 99%

“…CYP2A5, which is expressed in the lung, as well as in liver, kidney, and nasal mucosa (Su et al, 1996), is efficient in the bioactivation of NNK, as indicated by in vitro studies with recombinant CYP2A5 (Felicia et al, 2000;Jalas et al, 2003). Furthermore, NNK-induced lung tumorigenesis in mice was strongly inhibited by 8-methoxypsoralen (8-MOP) (Miyazaki et al, 2005), a compound often used as an inhibitor of CYP2A enzymes (Koenigs et al, 1997;Visoni et al, 2008;von Weymarn et al, 2005), although it is also capable of inhibiting CYP1A2 and CYP2E1 at higher concentrations (Labbe et al, 1987;Apseloff et al, 1991). However, direct proof for the role of CYP2A5 or CYP2A13 in mediating NNK bioactivation in vivo has yet to be obtained.…”

Section: Introductionmentioning

confidence: 99%

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Role of CYP2A5 in the Bioactivation of the Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Mice

Zhou¹,

D’Agostino²,

Xie³

et al. 2012

J Pharmacol Exp Ther

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The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen. Previously, we have demonstrated that NNK-induced lung tumorigenesis in mice depends on target-tissue bioactivation by pulmonary cytochrome P450 (P450) enzymes. The present study was designed to test the hypothesis that mouse CYP2A5 plays an essential role in NNK bioactivation in mouse lung. The role of CYP2A5 in NNK bioactivation was studied both in vitro and in vivo, by comparing the kinetic parameters of microsomal NNK metabolism and tissue levels of O 6 -methylguanine (O 6 -mG) (the DNA adduct highly correlated with lung tumorigenesis) between wild-type (WT) and Cyp2a5-null mice. In both liver and lung microsomes, the loss of CYP2A5 resulted in significant increases in the apparent K m values for the formation of 4-oxo-4-(3-pyridyl)butanone, which represents the reactive intermediate that produces O 6 -mG in vivo. The loss of CYP2A5 did not change circulating levels of NNK or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in mice treated intraperitoneally with NNK at either 20 or 100 mg/kg. However, the levels of lung O 6 -mG were significantly lower in Cyp2a5-null than in WT mice; the extent of the reduction was greater at the 20 mg/kg dose (ϳ40%) than at the 100 mg/kg dose (ϳ20%). These results indicate that CYP2A5 is the low-K m enzyme for NNK bioactivation in mouse lung. It is noteworthy that the remaining NNK bioactivation activities in the Cyp2a5-null mice could be inhibited by 8-methoxypsoralen, a P450 inhibitor used previously to demonstrate the role of CYP2A5 in NNK-induced lung tumorigenesis. Thus, P450 enzymes other than CYP2A5 probably also contribute to NNK-induced lung tumorigenesis in mice.

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Section: -Mop Dosementioning

confidence: 99%

Section: Effects Of 8-mop On the Clearance And Bioactivation Of Nnkmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of CYP2A5 in the Bioactivation of the Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Mice

Zhou¹,

D’Agostino²,

Xie³

et al. 2012

J Pharmacol Exp Ther

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show abstract

“…In humans, more than 80% of nicotine is metabolized to cotinine by cytochrome P450 2A6 (CYP2A6) [34] and cytochrome P450 2A5 (CYP2A5) [35] enzymes [36]. The physiologically active form of cotinine, the (-)-isomer, accumulates in the body as a result of tobacco exposure.…”

Section: Cotininementioning

confidence: 99%

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Echeverrı́a

Zeitlin

2012

CNS Neuroscience & Therapeutics

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SUMMARYTobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD. Alzheimer's disease: The Cholinergic System as a Therapeutic TargetAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]. The disease is characterized by extracellular accumulation of senile plaques, mainly composed of aggregated forms of the amyloid-beta peptide (Aβ), as well as intracellular accumulation of neurofibrillary tangles of the microtubule-associated protein tau [1]. These neuropathological changes are associated with structural brain abnormalities, inflammation, and cognitive impairment such as impairment of working memory in AD patients. The progressive loss of memory in AD patients correlates with increased levels of Aβ and the deterioration of the cholinergic system in the brain. The degenerative process involves a sequence of pathological events, including early degeneration of the cerebral basal forebrain and subsequent deterioration of the cortical cholinergic system [3,4]. This deterioration commonly includes a reduction in the levels of acetylcholine (ACh) and α3, α4, and α7 nicotinic ACh receptors (nAChRs) as well as a decrease in the activity of choline acetyltranferase in the brain [5].Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8]. The α7 subunit is highly expressed in the cortex, hippocampus, and hypothalamus [8], and has also been suggested to have functionally important expression in ...

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“…A coumarin derivative that may be present in celery extract was considered to be the furocoumarin 8-methoxypsoralen, since it is the only well-characterized inhibitor for CYP2A enzymes including CYP2A5 and CYP2A6 and as it also demonstrated distinct inhibition modes for CYP2A5 and CYP2A6 (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Celery extract inhibits mouse CYP2A5 and human CYP2A6 activities via different mechanisms

2016

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Abstract. Human cytochrome P450 (CYP) 2A6 participates in the metabolism of nicotine and precarcinogens, thus the deliberate inhibition of CYP2A6 may reduce cigarette consumption and therefore reduce the risk of developing the types of cancer associated with smoking. The inhibitory effects and mechanisms of celery (Apium graveolens) extract on mouse CYP2A5 and human CYP2A6 activity remain unclear. These effects were investigated in mouse and human liver microsomes using coumarin 7-hydroxylation in a probe reaction. Celery extract reduced CYP2A5 and CYP2A6 activities in vitro in a dose-dependent manner. In vivo experiments also showed that celery extract markedly decreased CYP2A5 activity. The inhibition of celery extract on CYP2A5 was time-and nicotinamide adenine dinucleotide phosphate (NADPH)-independent, and was markedly reduced by ultracentrifugation. Additionally, the inhibition of celery extract on CYP2A6 was time and NADPH-dependent. Levels of inhibition were characterized by a K i , the measure of the tightness of bonds between the enzyme and its inhibitor, of 266.4 µg/ml for CYP2A5, and a K i of 1,018 µg/ml and K inact of 0.3/min for CYP2A6. K inact is the maximal rate of enzyme inactivation at a saturating concentration of inhibitor. The coumarin derivative 5-methoxypsoralen present in celery extract did not solely to the inhibition of CYP2A5/6 activity. In conclusion, celery extract inhibited the levels of mouse CYP2A5 and human CYP2A6 activity via different mechanisms: Mixed competitive inhibition for CYP2A5 and mechanism-based inhibition for CYP2A6.

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Different modes of inhibition of mouse Cyp2a5 and rat CYP2A3 by the food-derived 8-methoxypsoralen

Cited by 14 publications

References 30 publications

Role of CYP2A5 in the Bioactivation of the Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Mice

Role of CYP2A5 in the Bioactivation of the Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Mice

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Celery extract inhibits mouse CYP2A5 and human CYP2A6 activities via different mechanisms

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