https://www.who.int/foodsafety/chem/2005_WHO_TEFs_ToxSci_2006.pdf

The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds.

An expert meeting was organized by the World Health Organization (WHO) and held in Stockholm on 15-18 June 1997. The objective of this meeting was to derive consensus toxic equivalency factors (TEFs) for polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and dioxinlike polychlorinated biphenyls (PCBs) for both human, fish, and wildlife risk assessment. Based on existing literature data, TEFs were (re)evaluated and either revised (mammals) or established (fish and birds). A few mammalian WHO-TEFs were revised, including 1,2,3,7,8-pentachlorinated DD, octachlorinated DD, octachlorinated DF, and PCB 77. These mammalian TEFs are also considered applicable for humans and wild mammalian species. Furthermore, it was concluded that there was insufficient in vivo evidence to continue the use of TEFs for some di-ortho PCBs, as suggested earlier by Ahlborg et al. [Chemosphere 28:1049-1067 (1994)]. In addition, TEFs for fish and birds were determined. The WHO working group attempted to harmonize TEFs across different taxa to the extent possible. However, total synchronization of TEFs was not feasible, as there were orders of a magnitude difference in TEFs between taxa for some compounds. In this respect, the absent or very low response of fish to mono-ortho PCBs is most noticeable compared to mammals and birds. Uncertainties that could compromise the TEF concept were also reviewed, including nonadditive interactions, differences in shape of the dose-response curve, and species responsiveness. In spite of these uncertainties, it was concluded that the TEF concept is still the most plausible and feasible approach for risk assessment of halogenated aromatic hydrocarbons with dioxinlike properties.

/pdf/toxic-equivalency-factors-tefs-for-pcbs-pcdds-pcdfs-for-595d73h716.pdf

Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife

Cortisol is the principal corticosteriod in teleost fishes and its plasma concentrations rise dramatically during stress. The relationship between this cortisol increase and its metabolic consequences are subject to extensive debate. Much of this debate arises from the different responses of the many species used, the diversity of approaches to manipulate cortisol levels, and the sampling techniques and duration. Given the extreme differences in experimental approach, it is not surprising that inconsistencies exist within the literature. This review attempts to delineate common themes on the physiological and metabolic roles of cortisol in teleost fishes and to suggest new approaches that might overcome some of the inconsistencies on the role of this multifaceted hormone. We detail the dynamics of cortisol, especially the exogenous and endogenous factors modulating production, clearance and tissue availability of the hormone. We focus on the mechanisms of action, the biochemical and physiological impact, and the interaction with other hormones so as to provide a conceptual framework for cortisol under resting and/or stressed states. Interpretation of interactions between cortisol and other glucoregulatory hormones is hampered by the absence of adequate hormone quantification, resulting in correlative rather than causal relationships.

Cortisol in teleosts: dynamics, mechanisms of action, and metabolic regulation

https://www.cell.com/cell-metabolism/pdf/S1550-4131(11)00420-7.pdf

Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation

Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy

Metabolic zonation of the liver: regulation and implications for liver function.

Glycogen in astrocytes: possible function as lactate supply for neighboring cells

Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes

Using primary rat hepatocyte cultures, the potency of several garlic-derived organosulfur compounds to inhibit cholesterol biosynthesisin toto as well as at early and late steps of this metabolic pathway was compared. Concerning early steps, allicin significantly inhibited incorporation of [14C]acetate into nonsaponifiable neutral lipids already at concentrations as low as 10 µM, while diallyl disulfide and allyl mercaptan were effective above 100 µM only. Likewise, inhibition in response to the two vinyl-dithiins started at 500 µM. If [14C]acetate was replaced by [14C]mevalonate, inhibition due to allicin, diallyl disulfide, and allyl mercaptan disappeared suggesting that HMGCoA-reductase was the target of inhibition. In contrast, for the vinyl-dithiins a stimulation of mevalonate incorporation was found. Concerning the late step, the potency to exert accumulation of lanosterol presumably by inhibiting lanosterol 14α-demethylase decreased in the order allicin>diallyl disulfide>allyl mercaptan=1,3-vinyl-dithiin≫1,2-vinyldithiin, the effect of the latter compound being close to zero. With respect to the total inhibition of [14C]acetate labeling of cholesterol, the half-maximal effective concentration-value of allicin was determined to be 17±2 µM compared to 64±7 µM for diallyl disulfide and to 450±20 µM for allyl mercaptan. Cytotoxicity as determined by the lactate dehydrogenase leakage assay was slightly higher for the two vinyl-dithiins than for diallyl disulfide and allyl mercaptan, but was apparent only at concentrations higher than 10 mM and, consequently, was irrelevant for the effects described. These results demonstrate that different garlic-derived organosulfur compounds interfere differently with cholesterol biosynthesis and, thus, may provoke multiple inhibition of this metabolic pathway in response to garlic consumption. The fact that allicin was the most effective inhibitor argues against the possibility that its degradation products, namely diallyl disulfide or allyl mercapatan, might mediate its effects, a possibility that might be true, however, in the case of the vinyl-dithiins.

Differential inhibitory effects of garlic-derived organosulfur compounds on cholesterol biosynthesis in primary rat hepatocyte cultures.

High-dose aqueous extracts from artichoke leaves were found to inhibit cholesterol biosynthesis from 14C-acetate in primary cultured rat hepatocytes in a concentration-dependent biphasic manner with moderate inhibition (approximately 20%) between 0007 and 01 mg/ml and more strong inhibition at 1 mg/ml Cytotoxic effects detected by lactate dehydrogenase leakage and the 3-[4, 5-dimethylthiazol-2-yl]-2,5-dephenyl tetrazolium bromide-assay were restricted to higher concentrations Replacement of 14C-acetate by 14C-mevalonate largely omitted the inhibiting effect of artichoke extracts indicating an inhibition at the level of hydroxymethylglutaryl-CoA-reductase However, no direct inhibition of this enzyme could be detected and no other enzymic steps later in the biosynthetic pathway for cholesterol seemed to be affected Instead, inhibition was found to occur in a time-dependent manner, to last for several hours even after washing out the extracts by fresh medium and to be fully reversible within 20 hr after removal of the extracts In addition, the stimulation of HMGCoA-reductase activity by insulin was efficiently blocked by the extracts, although other insulin-dependent phenomena, such as increased lactate production, were not influenced These results suggest an indirect modulation of hydroxymethylglutaryl-CoA-reductase activity as the most likely inhibitory mechanism of the artichoke extracts Screening of several known constituents of artichoke extracts revealed that cynaroside and particularly its aglycone luteolin were mainly responsible for inhibition, whereas chlorogenic acid was much less effective and caffeic acid, cynarin and other dicaffeoylquinic acids were without significant influence Indeed, luteolin also efficiently blocked the insulin effect on cholesterol biosynthesis In conclusion, these results demonstrate that artichoke extracts may inhibit hepatic cholesterol biosynthesis in an indirect but efficient manner and, thus, may contribute via this action to the recently confirmed hypolipidemic influence of this phytopharmacon in man

Rolf Gebhardt

Papers

Metabolic zonation of the liver: regulation and implications for liver function.

Glycogen in astrocytes: possible function as lactate supply for neighboring cells

Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes

Differential inhibitory effects of garlic-derived organosulfur compounds on cholesterol biosynthesis in primary rat hepatocyte cultures.

Inhibition of Cholesterol Biosynthesis in Primary Cultured Rat Hepatocytes by Artichoke (Cynara scolymus L.) Extracts