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Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Decreased rate of oxidation may be the cause also of fatty livers seen in vitamin PP or in vitamin B12 deficiencies (Di Luzio and Costales, 1964; Tandler et al., 1968). TG accumulation in these cases, however, is never heavy. Special attention should be given to fatty liver seen in rats after repeated intraperitoneal injection of 4-pentenoic acid (80 mg/kg b.w., 6–8 times during a fasting period of 48 h). It has been shown that this substance specifically blocks acyl-CoA.
Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Quantitatively (about 32% of a single dose), the most important oxidative metabolite of valproate appearing in urine is 3-oxo-valproate (2-propyl-3-keto-pentanoic acid). Qualitatively, delta-4 valproate (2-n-propyl-4-pentenoic acid) assumes toxicological importance since it has been shown that epoxidation of this metabolite generates a reactive product which causes hepatotoxicity.53 In contrast, the parent drug appears to be responsible for the teratogenic effects of this drug.54 Formation of the delta-4 unsaturated product is catalyzed by cytochrome P-450, an unusual function for this enzyme.55 Thus, hepatic toxicity can be influenced by drugs which induce or inhibit cytochrome P-450. Another point to consider is that each hydroxylation of valproate creates a chiral carbon. Whether or not this is important remains to be determined. An interesting effect of valproate on drug biotransformations is that it inhibits epoxide hydrolyase.56
Alternate Pathways of Steroid Biosynthesis and the Origin, Metabolism, and Biological Effects of Ring B Unsaturated Estrogens
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
B. R. Bhavnani, C. A. Woolever
Shimizu and Gut89 extended these investigations and demonstrated that incubation of cholesta-5,24-dien-3β-ol-2614C (desmosterol) (Figure 9) with calf adrenal preparations gave rise to pregnenolone and 14C-4-methyl-3-pentenoic acid. These results indicate that (1) the side-chain cleavage of demosterol at positions C-20 and C-22 could take place without the prior reduction of the Δ24-double bond and (2) desmosterol can act as a direct precursor for pregnenolone without first being converted to cholesterol.
Triterpenoids and steroids isolated from Anatolian Capparis ovata and their activity on the expression of inflammatory cytokines
Published in Pharmaceutical Biology, 2020
Isil Gazioglu, Sevcan Semen, Ozden Ozgun Acar, Ufuk Kolak, Alaattin Sen, Gulacti Topcu
It was significant that the all investigated extracts, prepared from different parts of C. ovata were found to be rich in sterols and terpenoids as well as long chain fatty acids Thus, fatty acid composition of the seeds of mature fruits (CHDFr) extract was analysed by GC-MS, and linoleic acid was found to be the major fatty acid (30.90%) as an omega-6 fatty acid, which is one of the essential fatty acids beside another omega-6 acid; arachidonic acid with a very low percentage. Other major acids were 2-methyl-2-pentenoic acid (19.10%), oleic acid (14.60%) and its trans isomer elaidic acid (t-Δ9-octadecenoic acid = t-oleic acid) (14.40%) while the relative abundance of palmitic acid was found to be 7.50% (Table 1). As an omega-3 fatty acid, only α-linolenic acid was present in this fatty acid composition, but with a fairly low percentage (1.03%). The fatty acid contents of the seeds of C. ovata and C. spinosa collected 11 different localities in Turkey have been previously investigated by Matthias and Ozcan (2005) in detail. In comparison to the fatty acid composition of those seeds with that of fruits extract of the C. ovata (CHDFr extract), some similarities were found (Table 1), especially for linoleic and oleic acid percentages.
Exploitation of the Ugi–Joullié reaction in drug discovery and development
Published in Expert Opinion on Drug Discovery, 2019
Stefano Gazzotti, Giulia Rainoldi, Alessandra Silvani
Among different Ugi-type reactions exploited for the synthesis of hemiasterline analogues, an Ugi-Joulliè-based protocol was reported, as shown in Figure 8. The effective replacement of multistep generation of sterically hindered amide functions with more reliable multicomponent assembly reactions was fully demonstrated. Tripiperideine 35 was chosen as the starting component, in order to avoid the possible epimerization of the isocyanoacetate 36 during formation of the cyclic imine. The Ugi-Joulliè reaction was carried out between 35, 36 and 5-pentenoic acid, to give the peptide intermediate 37 in good yield, which was then converted into tripeptide products in few steps. All the synthesized derivatives were tested in vitro for their cytotoxic activity against a panel of six human tumor cell lines, in comparison with the reference compound taltobulin [36]. Compounds 38 and 39 showed good activity though being 10-fold less active than taltobulin. They were also examined for their effects on tubulin polymerization and as inhibitors of the binding of [3H]vinblastine, [3H]dolastatin 10, and [3H]halichondrin B to tubulin. Both products were found to be active as tubulin inhibitors, although less active than taltobulin. To demonstrate the presumptive antimitotic activity, their effect on cell cycle progression in HeLa cells was also analyzed. Compound 38 was found very active, inducing cell cycle arrest at 5 nM, similarly to taltobulin.
Hyperammonemic encephalopathy without hepatic dysfunction due to treatment with valproate: four cases and a mini review
Published in Psychiatry and Clinical Psychopharmacology, 2018
Mustafa Dinçer, Abdullah Akgün, Şahin Bodur, Hesna Gül, Yasemin Taş Torun, Abdullah Bolu, Cemil Çelik, Miray Çetinkaya, Halil Kara, M. Ayhan Cöngöloğlu
Normally, 2-propyl-2-pentenoic acid (2-en-VPA), 3-hydroxy-2-propylpentanoic acid (3-OH-VPA) and 3-hydroxy-3-propylpentanoic acid (3-keto-VPA), which are non-toxic metabolites, are produced by β-oxidation. However, long-term or high-dose VPA use shifts metabolism from β-oxidation to omega-2 oxidation and increases the production of 2-propyl-4-pentanoic acid and propionic acid, which causes high levels of ammonia and hepatotoxicity. Propionic acid also reduces hepatic N-acetylglutamate (NAG) production, which inhibits mitochondrial CPS1 in the liver and consequently compromises the hepatic urea cycle. Increasing 4-en-VPA levels result in a similar result by reducing the availability of acetyl Co-A, an element of NAG. Another reason for the decrease in NAG production is the lack of carnitine. Inhibition of NAG from the end result of activation of Valproyl-CoA leads to an increase in ammonia level [52].