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Influence of Air on Essential Oil Constituents
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Darija Gajić, Gerhard Buchbauer
Allylic radicals are formed after the abstraction of the allylic hydrogen atoms, which can be achieved in three possible locations of the linalool molecule (Figure 29.12). The equilibrium between the alkyl radicals and their matching peroxyl radical can be affected by the difference in alkyl substitution on the peroxyl-bearing carbons. It is implied that the formation of secondary peroxyl radical Rb takes place in favor of the primary one Ra. Tertiary peroxyl radical Rd would be favored over the secondary one Rc for the same reason. Hence, Rb and Rd are considered to be the stable forms of peroxylradicals. This statement is in accordance with the hydroperoxides 12 and 13 being the only ones experimentally detected in the oxidation mixture of linalool. The hydrogen atom abstraction is more easily proceeded with the hydroperoxide 13 compared to the hydroperoxide 12, which confirms higher stability of the tertiary hydroperoxide 12 and thus explains its larger amount in the oxidation mixture.Possible decomposition of hydroperoxides leads to secondary oxidation products
Lipid peroxidation and its measurement
Published in Roger L. McMullen, Antioxidants and the Skin, 2018
Lipid peroxidation of unsaturated lipids and fatty acids results in the formation of conjugated diene structures. Normally, unsaturated fatty acids and lipids contain unconjugated dienes, where each double bond is separated by two single bonds. However, during the lipid peroxidation process these fatty acids and lipids undergo conversion where double bonds become separated by only one single bond, which is referred to as a conjugated diene. As shown in Figure 5.6, conversion of an unconjugated diene to a conjugated diene is the result of hydrogen atom abstraction and subsequent free radical formation. It is important to note that in the process of lipid peroxidation, conjugated dienes are intermediate products, which are eventually converted to lipid hydroperoxides.
Enzymes
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Bossard and Klinman (1986) tested a postulated mechanism for β-chlorophenethylamine inhibition of DβH in which enzyme-bound α-aminoacetophenone is generated, followed by an intramolecular redox reaction to yield ketone-derived radical cations as the enzyme inhibitor species. Phenylacetaldehyde was chosen to test this model because β-hydroxyphenyl acid aldehyde is expected to function as a reductant in a manner analogous to α-aminoacetophenone. Phenyl acid aldehyde exhibits the properties of a mechanism-based inhibitor. Some other amides were also found to be mechanism-based inhibitors-the product of hydroxylation is redox inactive. Therefore, they suggested that mechanism-based inhibitors are divided into two types: one type which undergoes hydroxylation prior to inactivation, and one type which only requires hydrogen atom abstraction.
Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation
Published in Drug Metabolism Reviews, 2020
Tingting Zhang, Jinqiu Rao, Wei Li, Kai Wang, Feng Qiu
It has been clarified that a reactive carbene intermediate derived from MDP is involved in the inactivation of P450 enzymes (Franklin 1971; Philpot and Hodgson 1971; Murray 2000; Kamel and Harriman 2013). Savinin (Table 3), a methylenedioxyphenyl lignan isolated from Acanthopanax chiisanensis, has been proven to be a mechanism-based inactivator of CYP3A4. It was speculated that the mechanism of inactivation of CYP3A4 by savinin was attributed to the formation of a reactive carbene intermediate. Specifically, hydrogen atom abstraction from the methylene carbon followed by hydroxylation at the bridging methylene group results in the formation of an unstable intermediate. On one hand, the resulting intermediate can undergo ring opening, hydrolysis and the subsequent loss of formic acid (HCOOH) to form a catechol (Figure 4, pathway A), which may further be oxidized to the reactive ortho-quinone metabolic intermediate, leading to covalent modification of the active sites of the enzyme. On the other hand, elimination of a water molecule from the intermediate should produce an acidic oxonium ion (Figure 4, pathway B) that upon deprotonation gives a carbene intermediate. This carbene species can coordinate with the heme iron of P450 enzymes, resulting in the formation of a carbene-iron complex (Kamel and Harriman 2013).
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
PUL undergoes GST-catalyzed direct GSH conjugation via Michael addition. Oxidation of the isopropyl methyl leads to formation of an allylic alcohol in which the hydroxyl group undergoes spontaneous intramolecular cyclization with the ketone to form a hemiketal, followed by dehydration to yield (R)-menthofuran (MF) (Figure 14(c)). Substitution of hydrogen with deuterium on the isopropyl methyl groups resulted in a significant decrease in both extent and severity of liver necrosis (Gordon et al. 1987). Investigations with selective deuterium labeled analogs suggested that upon initial hydrogen atom abstraction at the allylic methyl group, a tertiary radical is likely formed allowing for topomerization of the allylic methyl groups (Nelson et al. 1992) (Figure 14(d)). Studies with 18O incorporation showed that the oxygen atom in the furan ring of MF is derived exclusively from atmospheric O2, which is consistent with the mechanism of CYP-mediated hydrogen abstraction and oxygen rebound (Gordon et al. 1987). MF is a major metabolite of PUL both in vitro and in vivo. Like furans described above, MF is oxidized to a reactive 2,3-epoxymenthofuran leading to formation of γ-ketoenal which can be trapped by semicarbazide (Figure 14(c)). Both the furanoepoxide and γ-ketoenal likely contribute to covalent modification of hepatocellular proteins and hepatotoxicity of pennyroyal oil (Khojasteh et al. 2012; Gordon and Khojasteh 2015).
Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors
Published in Xenobiotica, 2018
Xiaoliang Zhuo, Ying-Zi Wang, Kap-Sun Yeung, Juliang Zhu, Xiaohua Stella Huang, Kyle E. Parcella, Kyle J. Eastman, John F. Kadow, Nicholas A. Meanwell, Yue-Zhong Shu, Benjamin M. Johnson
Next, potential mechanisms of NADPH-dependent hydroxylation and GSH conjugation on the 1,1-disubstituted cyclopropyl group in the HCV NS5B inhibitors were proposed based on these structural assignments (Figure 3). The initial step is proposed to be a P450-mediated hydrogen atom abstraction from one of the two equivalent cyclopropyl carbon atoms (Guengerich, 2001), yielding a cyclopropyl radical. Starting from the cyclopropyl radical, multiple distinct mechanisms could be invoked to explain the formation of GSH conjugates characterised by mass shifts of 305 and 323 Da. The cyclopropyl radical can react with a glutathione radical (GS.) to give rise to a conjugate with a molecular weight shift of 305 Da (pathway 1). Rebound of the hydroxyl radical onto the cyclopropyl radical forms a hydroxyl metabolite (P + 16 Da), completing a standard P450-catalysed carbon hydroxylation (pathway 2). The cyclopropyl moiety remains intact in these proposed pathways. Alternatively, opening of the cyclopropyl ring would relieve the aforementioned ring strain and give rise to two resonant propenyl radicals (3a and 3b), either of which could react with the inbound hydroxyl radical to form a substituted propenol products (pathway 3). The propenols would then be susceptible to nucleophilic attack by a glutathione, yielding regioisomeric glutathionylpropanol products (P + 323 Da) (pathways 4 and 5). On the other hand, the propenol derived from the tertiary propenyl radical (3a) may also eliminate a water molecule to form a carbonyl imine intermediate which further undergoes reductive conjugation by GSH to give rise to propenyl thioether conjugates (P + 305 Da) (pathway 6). The tertiary propenyl radical 3a may be more stable while the primary propenyl radical 3b is considered to be more reactive, thus favouring formation of conjugates with a certain regioselectivity. Unfortunately, the amounts of the conjugates isolated were insufficient to facilitate full structural characterisation by NMR, precluding our ability to differentiate among the isomers that are theoretically possible.