Aflatoxins would be expected to undergo biotransformations by 4 routes: (i) by hydroxylation of carbon atom at junction of the two fused furan rings, aflatoxin B1 is converted into aflatoxin M1, & this occurs to some extent in mammalian liver, (ii) oxidative o-demethylation of single aromatic methoxy-substituent gives aflatoxin P1 ... (iii) hydration of vinyl ether double bond would afford hemiacetals, & aflatoxin B1 is ... converted into aflatoxin hemiacetal B2a in guinea pig, mouse, & avian livers, (iv) & by reduction of cyclopentenone ring, dihydroaflatoxicol, but this biotransformation seems to be confined to avian species, & may be irrelevant to mammals.
In rhesus monkeys, injected ip ... the chloroform soluble urinary excretory products included aflatoxin M1 (2.3% of dose) & at least 3 other, unidentified ... compounds, as well as unchanged aflatoxin B1 (0.01-0.10%). Chloroform insoluble metabolites in urine were separated by ion exchange methods; major sub fraction consisted of aflatoxin P1 beta-glucuronide. Urinary aflatoxin P1 beta glucuronide represented about 20% of the dose; 17% as glucuronide, 3% as sulfate ester, & 1% as unconjugated phenol.
来源:Hazardous Substances Data Bank (HSDB)
代谢
人类肝脏匀浆体外代谢黄曲霉毒素B1的研究表明，黄曲霉毒素B1-2,3环氧物被产生。
Investigations of the in vitro metabolism of aflatoxin B1 by liver homogenates from humans ... indicate that aflatoxin B1-2,3 epoxide is produced ... .
Metabolism of Aflatoxin B1 was examined in isolated hepatocytes from rainbow trout. Intracellular DNA adduct formation was linearly related to aflatoxin B1 dose, & qualitatively similar to adducts formed in vivo. The rate of metabolism of adduct accumulation was constant during the first hr, after which an increased & gradual decrease in rate routinely occurred. Relative rates of production of the major unbound aflatoxin B1 metabolites aflatoxicol, aflatoxin M1 & polar conjugates, also remained constant over the 1st hr of preparation age, but subsequently changed in manner consistent with the changes in DNA binding.
Evaluation: There is sufficient evidence in humans for the carcinogenicity of naturally occurring mixtures of aflatoxins. There is sufficient evidence in humans for the carcinogenicity of aflatoxin B1. There is sufficient evidence in experimental animals for the carcinogenicity of naturally occurring mixtures of aflatoxins and aflatoxins B1, G1 and M1. Overall evaluation: Naturally occurring aflatoxins are carcinogenic to humans (Group 1). /Naturally occurring aflatoxins/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
黄曲霉毒素：已知的人类致癌物。
Aflatoxins: known to be human carcinogens. /Aflatoxins/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒案例。
Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Piperine is known to modify the biotransformation of drugs. The effect of piperine on the metabolic activation and distribution of (3)H-aflatoxin B1 in rats has been described. Piperine markedly inhibited liver microsome catalysed (3)H AFB1 binding to calf thymus DNA in vitro, in a dose dependent manner. Rats pretreated with piperine accumulated considerable (3)H AFB1 radioactivity in plasma and in the tissues examined as compared to the controls. However, piperine had no influence on hepatic (3)H AFB1-DNA binding in vivo, which could possibly be due to the null effect of piperine on liver cytosolic glutathione 5-transferase activity. Piperine treated rat liver microsomes demonstrated a tendency to enhance (3)H AFB1 binding to calf thymus DNA in vivo. The effect of piperine on AFB1 metabolism thus closely resembles the mode of action of SKF 525-A on biotransformation of foreign compounds.
...A Pekin duck model /was used/ to examine the effect of congenital duck hepatitis B virus infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to duck hepatitis B virus infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by ip injection once a wk from the third month posthatch until they were sacrificed (2.3 yr later). Two control groups of ducks not treated with AFB1 (one of which was infected with duck hepatitis B virus) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with duck hepatitis B virus and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with duck hepatitis B virus and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All duck hepatitis B virus carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No duck hepatitis B virus DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected.
Four days after /IP/ injection into monkeys, 5.6% of the dose was still retained by the liver, principally bound to liver proteins. After oral dose of aflatoxin B1, rhesus monkeys excreted about 20% as aflatoxin M1 during days 1-4; unchanged aflatoxin B1 accounted only for a small proportion & aflatoxin B1 beta-glucuronide accounted for 5% (3.3% as glucuronide & 1.2% as sulfate conjugate). Another 5% of the dose was excreted as aflatoxin B1 & aflatoxin M1 in the feces.
Aflatoxicol & aflatoxin B1 & M1 were found in tissues of kidney, liver, & muscle of feeder pigs fed estimated LD50 dose of B1 (0.1 mg/kg body wt) provided as rice culture of aspergillus flavus & of market wt pigs, fed naturally contaminated feed containing aflatoxin B1 at level of 400 ng/g from corn for 14 days. B1 & M1, when found in the feeding experiment, were at about the same levels in all tissues except the kidney, in which M1 was the most dominant aflatoxin.
Aflatoxin is excreted in the form of its metabolite aflatoxin M1 in the milk of lactating animals. In cattle given a single oral dose of aflatoxin, 85% of the total amount found in the milk and urine were detected in the first 48 hours after treatment. There was none in the milk after four days, nor in the urine or feces after six days. The total aflatoxin found in the milk was 0.39% of that ingested. ... Less than 0.6% of administered aflatoxin B1 was excreted in the milk. The amount of aflatoxin excreted in milk is unrelated to milk yield, and it disappears from the milk three to four days after the feeding of toxic meal is discontinued.
Evidence for the Probable Final Steps in Aflatoxin Biosynthesis
摘要：
The final steps in the biosynthesis of the potent environmental carcinogen aflatoxin B-1 (8) are believed to involve the oxidative cleavage and rearrangement of O-methylsterigmatocystin (7) with loss of a C-1-unit. The means by which this overall transformation occurs is not known and has been addressed using cell-free conversions of samples of radiolabeled 7 that were obtained by the incorporation of either [1-C-14]- or [2-C-14]acetate. The proportion of radioisotope detected in aflatoxin B-1 relative to that of the C-1-unit liberated (formaldehyde, formic acid, or carbon dioxide) was tested. [C-14]Carbon dioxide alone was isolated in the proper stoichiometry to limit the possible mechanisms that can be acting at the conclusion of this biosynthetic pathway.
The present invention encompasses novel triterpene compounds of general formula I
wherein
R3a R3b R11a R11b R31 and R32 are defined as in claim 1, which are suitable for the prevention and/or treatment of diseases mediated by 11β-HSD and the use thereof for preparing a medicament having the above-mentioned properties.
[EN] HETEROCYCLIC LSF INHIBITORS AND THEIR USES<br/>[FR] INHIBITEURS DE LSF HÉTÉROCYCLES ET LEURS UTILISATIONS
申请人：UNIV BOSTON
公开号：WO2021150835A1
公开（公告）日：2021-07-29
The present invention is directed to heterocyclic SV40 Factor (LSF) inhibitors and their uses. In some implementations, the present invention discloses small-molecule compounds of Formula (I). In some implementations, the compounds of Formula (I) are used in methods for inhibiting LSF in a subject. In some implementations, the compounds of Formula (I) are used in methods for treating cancer in a subject.
The present invention encompasses compounds of general formula (I) wherein R11a to R30 and X are defined as in claim 1, which are suitable for the treatment of and/or prevention of chronic inflammatory diseases, autoimmune diseases, skin diseases, bone diseases, metabolic diseases, infectious diseases and cancer.
COMPOUNDS AS MODULATOR OF JAK-STAT PATHWAY, METHODS AND APPLICATIONS THEREOF
申请人：UNIVERSITY OF MYSORE
公开号：US20160214968A1
公开（公告）日：2016-07-28
The present disclosure relates to compound of structural Formula I and a method for preparing said compounds. The disclosure further relates to a method of employing the Formula I compounds for modulation of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in cancer cells, and the corresponding use of compound of Formula I as anti-cancer agents.
Disclosed herein are methods, compositions, probes, assays and kits for identifying a lipid binding protein as a drug binding target. Also disclosed herein are methods, compositions, and probes for mapping a ligand binding site on a lipid binding protein, identification of lipid binding proteins, generating drug-lipid binding protein profiles, high throughput drug screening, and identification of drugs as potential lipid binding protein ligands.
