Mitochondrial Biotransformation of Drugs and Other Xenobiotics

2021 ◽  
Vol 22 ◽  
Author(s):  
Hilmi Orhan ◽  
Fuat Karakuş ◽  
Ali Ergüç
Keyword(s):  
Microsomal Fraction ◽  
Lipid Lowering ◽  
Metabolizing Enzymes ◽  
Xenobiotic Metabolizing Enzymes ◽  
Two Factors ◽  
Liver Microsomal Fraction ◽  
The Origin Of Life ◽  
Major Factors

: In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic. The opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered the centre of biotransformation reactions as the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalysed by mitochondria, where it is both an initiator and target of toxicity.

Effects of short-term saffron (Crocus sativus L.) intake on the in vivo activities of xenobiotic metabolizing enzymes in healthy volunteers

2019 ◽  
Vol 130 ◽  
pp. 32-43 ◽  
Author(s):  
Elias Begas ◽  
Maria Bounitsi ◽  
Thomas Kilindris ◽  
Evangelos Kouvaras ◽  
Konstantinos Makaritsis ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Crocus Sativus ◽  
Short Term ◽  
Metabolizing Enzymes ◽  
Xenobiotic Metabolizing Enzymes ◽  
Crocus Sativus L

scholarly journals Loss of haem in rat liver caused by the porphyrogenic agent 2-allyl-2-isopropylacetamide

1971 ◽  
Vol 124 (4) ◽  
pp. 767-777 ◽  
Author(s):  
F. De Matteis
Keyword(s):  
Rat Liver ◽  
Microsomal Fraction ◽  
Direct Evidence ◽  
Gradual Increase ◽  
Rapid Loss ◽  
Metabolizing Enzymes ◽  
Liver Microsomal Fraction ◽  
Green Pigments ◽  
Cytochrome P 450 ◽  
Increased Activity

1. The effect of a single dose of 2-allyl-2-isopropylacetamide on the cytochrome P-450 concentration in rat liver microsomal fraction was studied. The drug caused a rapid loss of cytochrome P-450 followed by a gradual increase to above the normal concentration. 2. The loss of cytochrome P-450 was accompanied by a loss of microsomal haem and by a brown–green discoloration of the microsomal fraction suggesting that a change in the chemical constitution of the lost haem had taken place. Direct evidence for this was obtained by prelabelling the liver haems with radioactive 5-aminolaevulate: the drug caused a loss of radioactivity from the haem with an increase of radioactivity in a fraction containing certain un-identified green pigments. 3. Evidence was obtained by a dual-isotopic procedure that rapidly turning-over haem(s) may be preferentially affected. 4. The loss of cytochrome P-450 as well as the loss of microsomal haem and the discoloration of the microsomal fraction were more intense in animals pretreated with phenobarbitone and were much less evident when compound SKF 525-A (2-diethylaminoethyl 3,3-diphenylpropylacetate) was given before 2-allyl-2-isopropylacetamide, suggesting that the activity of the drug-metabolizing enzymes may be involved in these effects. 5. The relevance of the destruction of liver haem to the increased activity of 5-aminolaevulate synthetase caused by 2-allyl-2-isopropylacetamide is discussed.

scholarly journals Hydroperoxide-induced chemiluminescence of the perfused lung

1980 ◽  
Vol 192 (1) ◽  
pp. 303-309 ◽  
Author(s):  
E Cadenas ◽  
I D Arad ◽  
A B Fisher ◽  
A Boveris ◽  
B Chance
Keyword(s):  
Microsomal Fraction ◽  
Light Emission ◽  
Time Dependent ◽  
Butyl Hydroperoxide ◽  
Time Dependent Process ◽  
Perfused Lung ◽  
Liver Microsomal Fraction ◽  
Alveolar Oedema ◽  
Hydroperoxide Concentration

Light-emission of the perfused lung is induced by t-butyl hydroperoxide, giving chemiluminescence yields that oscillate between 800 and 1500 counts/s depending on the site and position of the lung. The response of the perfused lung to infusion with different hydroperoxides gives a pattern similar to that observed with the liver microsomal fraction; ethyl hydroperoxide shows a much higher chemiluminescence yield than the tertiary (t-butyl and cumene)hydroperoxides. Alveolar oedema affected the light-emission of the perfused lung depending on the time at which oedema developed, decreasing light emission on infusion of hydroperoxide in the oedematous lung and increasing it when oedema appeared after the maximal chemiluminescence yield was already achieved. Paraquat, administered in vivo, augmented light-emission by approximately 2-fold. The effect of paraquat was a time-dependent process. Lung chemiluminescence, compared with liver chemiluminescence, needed higher hydroperoxide concentration to induce light-emission.

The effect of modifying the nanostructure of gelatin fiber scaffolds on early angiogenesis in vitro and in vivo

2021 ◽  
Author(s):  
Yanyi Liu ◽  
Xiaoxue Wang ◽  
Fei Hu ◽  
Xiaohui Rausch-fan ◽  
Thorsten Steinberg ◽  
...  
Keyword(s):  
Tissue Regeneration ◽  
Fiber Diameter ◽  
Early Stage ◽  
Fiber Membrane ◽  
Soft Tissue Regeneration ◽  
Two Factors ◽  
Fiber Scaffolds

Abstract Early angiogenesis is one of the key challenges in tissue regeneration. Crosslinking mode and fiber diameter are critical factors to affect the adhesion and proliferation of cells. However, whether and how these two factors affect early angiogenesis remain largely unknown. To address the issue, the optimal crosslinking mode and fiber diameter of gelatin fiber membrane for early angiogenesis in vivo and in vitro were explored in this work. Compared with the post crosslinked gelatin fiber membrane with the same fiber diameter, the 700 nm diameter in situ crosslinked gelatin fiber membrane was found to have smaller roughness (230.67 ± 19 nm) and stronger hydrophilicity (54.77 ± 1.2°), which were suitable for cell growth and adhesion. Moreover, the in situ crosslinked gelatin fiber membrane with a fiber diameter of 1000 nm had significant advantages in early angiogenesis over the two with fiber diameters of 500 and 700 nm by up-regulating the expression of Ang1, VEGF, and integrin-β1. Our findings indicated that the in situ crosslinked gelatin fiber membrane with a diameter of 1000 nm might solve the problem of insufficient blood supply in the early stage of soft tissue regeneration and has broad clinical application prospects in promoting tissue regeneration.

The impact of sesquiterpenes β-caryophyllene oxide and trans-nerolidol on xenobiotic-metabolizing enzymes in mice in vivo

Xenobiotica ◽  
2017 ◽  
Vol 48 (11) ◽  
pp. 1089-1097 ◽  
Author(s):  
Kateřina Lněničková ◽  
Hana Svobodová ◽  
Lenka Skálová ◽  
Martin Ambrož ◽  
Filip Novák ◽  
...  
Keyword(s):  
Caryophyllene Oxide ◽  
Metabolizing Enzymes ◽  
Xenobiotic Metabolizing Enzymes ◽  
The Impact

scholarly journals The apparent absence of involvement of biotin in the vitamin K-dependent carboxylation of glutamic acid residues of proteins

1977 ◽  
Vol 163 (1) ◽  
pp. 39-43 ◽  
Author(s):  
P A Friedman ◽  
M A Shia
Keyword(s):  
Glutamic Acid ◽  
Vitamin K ◽  
Microsomal Fraction ◽  
Male Rats ◽  
Biotin Deficiency ◽  
Deficient Diet ◽  
Carboxylase Activity ◽  
Liver Microsomal Fraction

The mechanism of the vitamin K-dependent post-translational carboxylation of the gamma-carbon atom of glutamic acid residues in proteins remains obscure. Experiments were performed in vivo and in vitro in an attempt to establish a role for biotin in the transfer of the carboxyl group. Weanling male rats were fed on a biotin-deficient diet until severe biotin deficiency was induced. Their degree of biotin deficiency was documented by assaying for liver acetyl-CoA carboxylase activity, which was about 15% of normal. However, one-stage and two-stage prothrombin times measured on the plasmas were normal. In addition, the liver microsomal fraction did not contain any more prothrombin precursor than did that of normal rat liver. Experiments were done in vitro in which vitamin K-dependent fixing of 14CO2 was measured in the liver microsomal fraction from vitamin K-deficient male rats in the presence or absence of avidin. No evidence for an avidin-sensitive critical biotin-containing site was obtained. Thus neither series of experiments suggests a role for biotin; the data are compatible with carboxyl transfer occurring either through a carboxylated vitamin K intermediate; or via a yet to be identified intermediate, or perhaps via CO2 itself.

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