Cell specificity in metabolic activation of aflatoxin B1 and benzo(a)pyrene to mutagens for mammalian cells

Nature ◽  
1978 ◽  
Vol 276 (5685) ◽  
pp. 277-280 ◽  
Author(s):  
ROBERT LANGENBACH ◽  
HEATHER J. FREED ◽  
DINA RAVEH ◽  
ELIEZER HUBERMAN
Keyword(s):  
Aflatoxin B1 ◽  
Mammalian Cells ◽  
Metabolic Activation ◽  
Cell Specificity

Cell-Specific Chemical Delivery Using a Selective Nitroreductase–Nitroaryl Pair

2018 ◽  
Author(s):  
Todd D. Gruber ◽  
Chithra Krishnamurthy ◽  
Jonathan B. Grimm ◽  
Michael R. Tadross ◽  
Laura M. Wysocki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Mammalian Cells ◽  
Target Cells ◽  
Specific Chemical ◽  
E Coli ◽  
Enzyme Substrate ◽  
Cell Specificity ◽  
General Chemical ◽  
Increased Activity ◽  
Enzyme Variant

<p>The utility of<b> </b>small molecules to probe or perturb biological systems is limited by the lack of cell-specificity. ‘Masking’ the activity of small molecules using a general chemical modification and ‘unmasking’ it only within target cells could overcome this limitation. To this end, we have developed a selective enzyme–substrate pair consisting of engineered variants of <i>E. coli</i> nitroreductase (NTR) and a 2‑nitro-<i>N</i>-methylimidazolyl (NM) masking group. To discover and optimize this NTR–NM system, we synthesized a series of fluorogenic substrates containing different nitroaromatic masking groups, confirmed their stability in cells, and identified the best substrate for NTR. We then engineered the enzyme for improved activity in mammalian cells, ultimately yielding an enzyme variant (enhanced NTR, or eNTR) that possesses up to 100-fold increased activity over wild-type NTR. These improved NTR enzymes combined with the optimal NM masking group enable rapid, selective unmasking of dyes, indicators, and drugs to genetically defined populations of cells.</p>

scholarly journals The Mechanism Underlying the Extreme Sensitivity of Duck to Aflatoxin B1

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Kuntan Wu ◽  
Minjie Liu ◽  
Huanbin Wang ◽  
Shahid Ali Rajput ◽  
Yajing Shan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Aflatoxin B1 ◽  
High Sensitivity ◽  
Metabolic Activation ◽  
Cytochrome P450s ◽  
Economic Losses ◽  
Metabolic Detoxification ◽  
Glutathione S Transferases ◽  
Extreme Sensitivity ◽  
Mutual Conversion

Most metabolites of aflatoxin B1 (AFB1), especially exo-AFB1-8,9-epoxide (AFBO), can induce the production of reactive oxygen species (ROS) to vary degrees, causing oxidative stress and liver damage, and ultimately induce liver cancer in humans and animals. Duck is one of the most sensitive animals to AFB1, and severe economic losses are caused by duck AFB1 poisoning every year, but the exact mechanism of this high sensitivity is still unclear. This review highlights significant advances in our understanding of the AFB1 metabolic activation, like cytochrome P450s (CYPs), and AFB1 metabolic detoxification, like glutathione S-transferases (GSTs) in poultry. In addition, AFB1 may have other metabolic pathways in poultry, such as the mutual conversion of AFB1 and aflatoxicol (AFL) and the process of AFBO to produce AFB1-8,9-dihydrodiol (AFB1-dhd) and further metabolize it into detoxification substances. This review also summarized some exogenous regulatory substances that can alleviate AFB1-induced oxidative stress.

Cell-Specific Chemical Delivery Using a Selective Nitroreductase–Nitroaryl Pair

2018 ◽  
Author(s):  
Todd D. Gruber ◽  
Chithra Krishnamurthy ◽  
Jonathan B. Grimm ◽  
Michael R. Tadross ◽  
Laura M. Wysocki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Mammalian Cells ◽  
Target Cells ◽  
Specific Chemical ◽  
E Coli ◽  
Enzyme Substrate ◽  
Cell Specificity ◽  
General Chemical ◽  
Increased Activity ◽  
Enzyme Variant

<p>The utility of<b> </b>small molecules to probe or perturb biological systems is limited by the lack of cell-specificity. ‘Masking’ the activity of small molecules using a general chemical modification and ‘unmasking’ it only within target cells could overcome this limitation. To this end, we have developed a selective enzyme–substrate pair consisting of engineered variants of <i>E. coli</i> nitroreductase (NTR) and a 2‑nitro-<i>N</i>-methylimidazolyl (NM) masking group. To discover and optimize this NTR–NM system, we synthesized a series of fluorogenic substrates containing different nitroaromatic masking groups, confirmed their stability in cells, and identified the best substrate for NTR. We then engineered the enzyme for improved activity in mammalian cells, ultimately yielding an enzyme variant (enhanced NTR, or eNTR) that possesses up to 100-fold increased activity over wild-type NTR. These improved NTR enzymes combined with the optimal NM masking group enable rapid, selective unmasking of dyes, indicators, and drugs to genetically defined populations of cells.</p>

scholarly journals Metabolic activation of aflatoxin B1 to aflatoxin B1-8,9-epoxide in woodchucks undergoing chronic active hepatitis

1997 ◽  
Vol 73 (4) ◽  
pp. 587-591 ◽  
Author(s):  
Mekonnen Gemechu-Hatewu ◽  
Karl-Ludwig Platt ◽  
Franz Oesch ◽  
Hans-Jörg Hacker ◽  
Peter Bannasch ◽  
...  
Keyword(s):  
Chronic Active Hepatitis ◽  
Aflatoxin B1 ◽  
Metabolic Activation
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