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Anwar Mohamed Louisville

Abstract: Anwar Gamal Mohamed Louisville -
Regulation of CYP1A1

 

Anwar Gamal Mohamed realized that Cytochrome P450 1A1 (CYP1A1) may be a internal organ and extra hepatic protein that

is regulated by the aryl organic compound receptor sign pathway. With the

growing human exposure to serious metals, rising proof suggests that

heavy metals exposure alter CYP1A1 protein activity. serious metals regulate

CYP1A1 at completely different levels of its aryl organic compound receptor sign pathway

in a metal- and species-dependent manner. The importance of CYP1A1

emerges from the actual fact that it's been continuously related to the metabolism

of pro-carcinogenic compounds to extremely cancer metabolites. However,

recently CYP1A1 has gained standing beside alternative haemoprotein P450

enzymes within the metabolism of medication and mediating drug–drug interactions.

In addition, CYP1A1 has become a therapeutic tool for the bio activation

of prod rugs, notably cytotoxic agents. during this review, we tend to shed light-weight on

the impact of seven serious metals, particularly arsenic, mercury, lead, cadmium,

chromium, copper and atomic number 23, on CYP1A1 and therefore the consequences on

drug metabolism.

Keywords: aryl organic compound receptor, CYP1A1, drug metabolism, serious metals

 

1.Introduction

Anwar Gamal Mohamed research shows that The aryl organic compound receptor (AhR) may be a member of basic-helix-loop-helix

(bHLH)/Per-ARNT-Sim (PAS) family of transcription proteins. Inactive AhR

resides within the living substance guaranteed to 2 90-kDa heat-shock proteins (HSP90), the

23-kDa heat shock supermolecule (p23) and hepatitis B virus X-associated super molecule two

(XAP2). On matter binding, the AhR-ligand advanced dissociates from the protoplasm advanced and translocate to the nucleus wherever it associates with the aryl

hydrocarbon nuclear trans locator (ARNT) [1]. the full advanced then acts as a

transcription issue that binds to a selected DNA recognition sequence, termed

the xenobiotic responsive component (XRE), situated within the promoter region of a

number of AhR-regulated genes. Among these genes area unit those coding variety

of drug metabolizing enzymes, as well as four clinical test enzymes (cytochrome P450

1A1 (CYP1A1), CYP1A2, CYP1B1 and CYP2S1) and 4 phase II clinical trial enzymes

(NAD(P)H: benzoquinone oxidoreductase-1 (NQO1), glutathione-S-transferase A1,

cytosolic organic compound dehydrogenase-3 and UDP-glucuronosyl transferees 1A6) [1,2].

In the gift review, current information concerning the impact of serious metals, in

particular, arsenic (As3+), mercury (Hg2+), lead (Pb2+), metal (Cd2+), Cr (Cr6+), copper (Cu2+) and atomic number 23 (V5+) on CYP1A1 is reviewed. In

addition, its consequence on drug metabolism is mentioned.

 

2. The AhR structure

According to Anwar Gamal Mohamed ; The AhR super molecule contains many domains vital for its perform. The bHLH

motif situated within the N-terminus of the supermolecule contains 2 functionally distinctive

Regulation of CYP1A1 by serious metals and consequences for drug metabolism

and extremely preserved domains [3]. the primary is that the basic

region, that is especially concerned within the binding of AhR to

DNA. The second is that the helix-loop-helix domain, which is

embroiled in protein–protein interactions. Members of the

bHLH family additionally embody fruit fly biological time supermolecule amount (Per), the ARNT and therefore the fruit fly animal tissue

protein single minded (Sim) [4-6]. The AhR supermolecule contains

two PAS domains, PAS-A and PAS-B. These PAS domains

are concerned in secondary interactions with alternative PAS containing proteins, like AhR and ARNT [5,6]. in addition,

the PAS-B domain contains the AhR matter binding website [7].

Finally, a aminoalkanoic acid (Q) made region situated inside the C-terminal

region was found to be to blame for transcriptional activation

on AhR binding to the DNA [3

].

Within the living substance, HSP90s move with the PAS-B

and bHLH domains of the AhR, maintaining the high

affinity matter binding conformation of the AhR, and

repressing its intrinsic DNA-binding activity [8]. The autocoid E synthase three (p23) is believed to stabilize the interaction

between HSP90s and therefore the AhR [9], shield the receptor from

being degraded through chemical change, and stop the premature

binding of AhR to ARNT. On the opposite hand, XAP2 interacts

with the C-terminal of HSP90 and therefore the nuclear localization

sequence of the AhR, preventing inappropriate trafficking of

the unliganded receptor to the nucleus [10,11].

 

3.CYP1A1 regulation

Dr. Anwar Gamal Mohamed Archives said that  Among the CYP450s, CYP1A1 has received considerab

attention as a result of it's extremely evoked by a broad vary o

xenobiotics like polycyclic aromatic hydrocarbons (PAH

and halogenated aromatic hydrocarbons (HAHs) throug

the AhR–XRE transcription pathway [12]. CYP1A1 is capab

of producing polar, deadly or maybe cancer metabolit

from varied AhR ligands, as well as PAHs. Dissection o

the class CYP1A1 factor discovered many regulator

elements that modulate its expression. the primary is that the XRE

several of that area unit localized one KB upstream of the transcrip

tion begin website all told class CYP1A1 genes [13]. Second

there area unit 3 corticosteroid responsive parts (GREs) i

the human, rat and mouse CYP1A1 factor within the 1st DNA

responsible for the modulation of PAHs-induced CYP1A

expression by corticosteroids [14]. Last, the presence of

negative restrictive component, situated between -560 and -83

bp, inhibits the constituent expression of CYP1A1 due t

an interaction with the nuclear transcription facto

Oct-1 [13].

 

4. AhR cross-talk with NRs

Dr. Anwar Gamal Mohamed Archives showed that For the past few decades, in depth studies are

made to correlate the impact of various nuclear receptor

(NR) inducers to the activation of AhR, that has been

Termed cross-talks. Of interest, there are many

Attempts to elucidate these cross-talks. Generally, there are

several theories explaining these cross-talks: that's, the competi

tive binding of various NRs to a DNA-binding website, selective

Dimerization with alternative NRs before the DNA-binding step

and finally binding of various ligands that might most likely

affect the accomplishment of a large array of co-activators.

Therefore, within the following section, we tend to specialize in four NRs

cross-talks with AhR, namely, nuclear issue blood corpuscle 2-related

factor-2 (Nrf2), steroid hormone receptor (ER), glucocorticoid

receptor (GR), retinoid activated receptors (RARs) and

retinoid X receptors (RXRs).

 

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