Inhibition of CYP450 enzymes

Effect of natural analogues of trans-resveratrol on cytochromes P4501A2 and 2E1 catalytic activities.

Mikstacka R, Rimando AM, Szalaty K, Stasik K, Baer-Dubowska W.

Department of Pharmaceutical Biochemistry, University of Medical Sciences, Poznan, Poland.

The aim was to assess the inhibitory effect of a series of naturally occurring trans-resveratrol analogues on cytochromes P450, namely CYP1A2 and CYP2E1, in vitro in order to analyse any structure-activity relationships. 3,5-Dimethoxy-4'-hydroxy-trans-stilbene (pterostilbene), 3,4',5-trimethoxy-trans-stilbene (TMS), 3,4'-dihydroxy-5-methoxy-trans-stilbene (3,4'-DH-5-MS) and 3,5-dihydroxy-4'-methoxy-trans-stilbene (3,5-DH-4'-MS) inhibited the activity of CYP1A2, with K(i) = 0.39, 0.79, 0.94 and 1.04 microM, respectively. Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene) was the least potent inhibitor of CYP1A2 with a K(i) = 9.67 microM. Piceatannol and TMS in the concentration range 1-100 microM did not inhibit CYP2E1 activity. The activity of this enzyme likewise was not significantly influenced by pterostilbene and 3,5-DH-4'-MS with IC(50) > 100 microM, whereas 3,4'-DH-5-MS appeared to be a moderately potent, competitive inhibitor of CYP2E1 (K(i) = 42.6 microM). Structure-activity relationship analysis leads to the conclusion that the substitution of hydroxy groups of resveratrol with methoxy groups increases the inhibition of CYP1A2, yet the number and position of methylation are not essential. However, the 4'-hydroxy group in trans-resveratrol and its analogues may play an important role in the interaction with a binding site of CYP2E1.

PMID: 16684708 [PubMed - in process]

Jesus Christ! It seems as though we are all going to need degrees in pharmacology/biochemistry to understand the research.

Selected inducers, inhibitors and substrates of CYP1A2
inducers: broccoli, brussel sprouts, chargrilled meat, insulin, modafinil, nafcillin, omeprazole, tobacco
inhibitors: amiodarone, cimetidine, fluoroquinolones (ciprofloxacin, etc), fluvoxamine, interferon, methoxsalen
substrates: amitriptyline, caffeine, clomipramine, clozapine, cyclobenzaprine, estradiol, fluvoxamine, haloperidol, imipramine, mexiletine, naproxen,
olanzapine, ondansetron, paracetamol, propranolol, riluzole, ropivacaine, tacrine, theophylline, tizanidine, verapamil, warfarin, zileuton,
zolmitriptan

Selected inducers, inhibitors and substrates of CYP2E1[B/]
inducers: acetone, ethanol, isoniazid
inhibitors: cimetidine, disulfiram, (isoniazid)?
substrates: anaesthetics (halothane, isoflurane, etc), dapsone, paracetamol, theophylline

Inhibition of the CYP1A2 family can't be bad because its activity converts procarcinogens to cancinogenic compounds. As for CYP2E1....here is some information on CYP2E1

CYP2E1: Biochemistry, Toxicology, Regulation and Function in Ethanol-Induced Liver Injury
Authors: Kessova I.1; Cederbaum A.I.1
Source: Current Molecular Medicine, Volume 3, Number 6, September 2003, pp. 509-518(10)
Publisher: Bentham Science Publishers

Abstract:
Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. CYP2E1 is of interest because of its ability to metabolize and activate many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. [b]CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of HepG2 cell lines developed to constitutively express the human CYP2E1 in assessing the actions of CYP2E1. Regulation of CYP2E1 is quite complex and will be briefly reviewed. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

Keywords: cyp2e1; ethanol-induced liver injury; chronic alcohol treatment; cyp2e1-dependent oxidative stress

Document Type: Review article

Again, inhibition of CYP2E1 does not seem to be a bad thing.

CYP2E1 is of interest because of its ability to metabolize and activate many toxicological substrates, including ethanol, to more reactive, toxic products.

Does this mean I can drink more without getting drunk? If so, I could win quite a bit of money at the local pub in drinking competitions. [tung] Somehow I do not think this applies or else you could red wine and not get pissed. All it takes is one glass of red wine for me and I am anyones

CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical.

Bad CYP2E1. Bad CYP!

Now all we need to do is find a decent resvertrol supplement.

What are peoples thoughts

many people here prefer longevinex.

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Yes I am aware of that. I have read the posts of longevinex.

OK, no more alcohol AT ALL.

http://tinyurl.com/llg5r

Quote:
> This is the table I compiled from a variety of sources, most of which
> I have references for and will post when I organize. D means
> decreases, or inhibits, and I means increases or activates the P450's.
> Hu means the study was on in humans, or at least on humans cells. I
> can't remember which.

> P-450 EFFECTS OF OTHER SUBSTANCES

Salt D
> Angelica Dihurica D
> ascorbyl palmitate D 600mg/day Hu
> benzyl isothiocyanate D
> (a cruciferous vegetable extract)
> Brussel sprouts I
> Cat's claw D
> Chamomile D
> Cholesterol I
> Chinese Medicines (many) D
> Danshen D
> Diesel exhaust I
> Echinacea D
> Ethanol I+D
> Evening Primrose oil (cis linoleic acid) <10
> Fat I
> Flavone D .15 Hu
> Garlic (allicin) D
> <10
> Ginseng D
> Ginkoe Biloba (ginkgolic acids I and II) D <10
> Grape fruit D 300ml/day
> Green tea D 75 Hu
> Goldenseal D
> Kava D
> <10
> Lycorice D
> Lipoic acid D .25g/kg in fish
> Meat, fried I
> Menthol D
> Hu
> Milk Thistle D
> Naringin D
> Peppermint oil D
> 600mg/day Hu
> Piperine D
> Quercetin D
> Resveratrol D 11
> Rutaecarpine (Chinese supplement) D
> 39nmole
> St John's Wort D .5 to 1 for certain
> components
> Tangeretin D .16Hu
> Vitamin A D
> Vitamin D I
> Wild Cherry D

you all do realize that cytochrome P450s are responsible for the hydroxylation of a vast array of toxic substances so they become soluble and can therefore be excreted. We have these enzymes for a reason.

you all do realize that cytochrome P450s are responsible for the hydroxylation of a vast array of toxic substances so they become soluble and can therefore be excreted.  We have these enzymes for a reason.

THE WINNER [thumb]

My thoughts are on CYP450? It's one of my favorite enzymes! My true favorite isoenzyme is CYP 2D6 -- don't let 450 know though...you know how those enzymes are. [wis]

The problem is the complexity of the cytochrome P450 system.

you all do realize that cytochrome P450s are responsible for the hydroxylation of a vast array of toxic substances so they become soluble and can therefore be excreted. We have these enzymes for a reason.

Totally agree. However, artificial manipulation of the P450 system should be treated with caution because there is much we do not know.

For those interested

Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.

Moon YJ, Wang X, Morris ME.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA.

Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo Biloba, Soy Isoflavones, and Milk Thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. Additionally, they are extremely safe and associated with low toxicity, making them excellent candidates for chemopreventive agents. The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. Importantly, the effects of flavonoids on enzymes are generally dependent on the concentrations of flavonoids present, and the different flavonoids ingested. Due to the low oral bioavailability of many flavonoids, the concentrations achieved in vivo following dietary administration tend to be low, and may not reflect the concentrations tested under in vitro conditions; however, this may not be true following the ingestion of herbal preparations when much higher plasma concentrations may be obtained. Effects will also vary with the tissue distribution of enzymes, and with the species used in testing since differences between species in enzyme activities also can be substantial. Additionally, in humans, marked interindividual variability in drug-metabolizing enzymes occurs as a result of genetic and environmental factors. This variability in xenobiotic metabolizing enzymes and the effect of flavonoid ingestion on enzyme expression and activity can contribute to the varying susceptibility different individuals have to diseases such as cancer. As well, flavonoids may also interact with chemotherapeutic drugs used in cancer treatment through the induction or inhibition of their metabolism.

Publication Types:

    * Review


PMID: 16289744 [PubMed - indexed for MEDLINE]

Therefore it would be advantageous to have inherited the double mutation that impairs catalytic activity (normally a mutation that decreases activity is disadvantageous) on the CYP2E1 gene, particularly if you are a drinker and a smoker (it is also induced by nicotine)..

We have these enzymes for a reason.

Unfortunately the reason for their presence is not always associated with health and longevity..

Hi people,
Sorry for the potential tangent, but if anyone has any insight into my misadventures with selegiline, methylphenidate, and cytochrome; please add reply or PM me. (even if to tell my I'm barking up the wrong tree here)

woof.

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Add Bacopa to that list of inhibitors. Not sure what this means but there's a list of drugs out there that one should avoid inhibitors on.