In Vivo Toxicity

The action of uncouplers is to dissociate oxidation in the respiratory chain from phosphorylation. These compounds are toxic in vivo, causing respiration to become uncontrolled, since the rate is no longer limited by the concentration of ADP or Pj. The uncoupler that has been used most frequently is 2,4-dinitrophenol, but other compounds act in a similar manner. The antibiotic oligomycin completely blocks oxidation and phosphorylation by acting on a step in phosphorylation (Figures 12-7 and 12-8). 

Andersen ME, Gargas ML, Jones RA, et al. 1980. Determination of the kinetic constants for metabolism of inhaled toxicants in vivo using gas uptake measurements. Toxicol Appl Pharmacol 54 100-116. 

Petry, T.W., Wolfgang, G.H., Jolly, R.A., Ochoa, R. and Donarski, W.J. (1992). Antioxidant-dependent inhibition of diquat-induced toxicity in vivo. Toxicology 74, 33-43. 

Chlorpromazine (CPZ) and pentoxifylline (PTX) were shown to inhibit TNF release and improve survival during murine endotoxemia (Gl). CPZ (M25) and epinephrine (PI6) pretreatment markedly up-regulated IL-10 production induced by LPS, a phenomenon also observed with cyclosporine (Dl). PTX pretreatment did not affect LPS-induced IL-10 release. Thus, TNF and IL-10 can be differentially regulated during murine endotoxemia. The sustained or even increased production of IL-10 could play a role in the protective effects of these drugs against LPS toxicity in vivo. 

In spite of a high reactivity of 3-carotene in free radical reactions and marked antioxidant effects in in vitro systems, 3-carotene did not show itself as an effective in vivo antioxidant. Furthermore, recent clinical trials suggested that the administration of 3-carotene may be useless or even harmful to patients with heart and some other diseases, especially to smokers. One might suspect that one of the major reasons of toxic in vivo effects of 3-carotene might be the formation of prooxidative compounds during 3-carotene oxidation. In contrast to... 

It was initially argued that the best potential PTK inhibitors would be compounds that compete for the substrate in the kinase binding domain. It was argued that such compounds would be less toxic than ATP mimics since they bind to those domains at the kinase site that are less conserved than the substrate binding domains. Indeed tyrphostins like AG 490 which blocks Jak-2 [10] and AG 556 which possesses anti-inflammatory properties have been shown to be highly non-toxic in vivo [34-37]. 

FIGURE 17.5. The use of in vitro techniques in performing interspecies comparisons. 1, correlation of in vitro with in vivo observations 2, development of parallel in vitro systems in man 3, comparison of in vivo sensitivity of different species 4, potential toxicity in vivo 5, comparison of in vivo sensitivity of different species. 

Maduh EU, Nealley EW, Song H, et al. 1995. A protein kinase C inhibitor attenuates cyanide toxicity in vivo. Toxicology 100 129-137. 

Niknahad H, O Brien PJ. 1996. Antidotal effect of dihydroxyacetone against cyanide toxicity in vivo. Toxicology and Applied Pharmacology 138 186-191. 

Sayes C, Marchione A, Reed K, Warheit DB (2007) Comparative pulmonary toxicity assessments of C60 water suspensions in rats Few differences in fullerene toxicity in vivo in contrast to in vitro profiles. Nano Lett. 7 2399-2403. 

O. van Tellingen, T. Buckle, J.W. Jonker, M.A. van der Valk, and J.H. Beijnen. P-glycoprotein and Mrpl collectively protect the bone marrow from vincristine-induced toxicity in vivo. Br J Cancer. 89 1776-1782 (2003). 

Chlorodibromomethane was not geno-toxic in vivo but gave positive results in a number of in vitro assays. ... 

Anyhow, a combination of the Scatchard technique and Raman spectroscopy shows (i) that SOAz actually interacts with DNA at the level of ribose backbones and (ii) that this kind of interaction does not drastically modify the DNA secondary structure, ethidium bromide encountering no more difficulty to intercalate between DNA plates SOAz being grafted or not on the nucleic acid. Thus, the behaviour of MYKO 63 and of SOAz appears quite different with respect to their mode of interaction with DNA despite their close chemical and molecular structure. This surprising observation may be of interest for understanding why SOAz does not induce any cumulative toxicity in vivo in contrast with MYKO 63. 

Pseudopederin (148) and pederone (149) display the phytoinhibition, the dermotoxic, and toxic endoperitoneal action in mice, as well as the inhibitory activities on various animal and human cell strains. However, their effects are much less than those of pederin (147). Pederone (149) causes less endoperitoneal toxicity in vivo than the other two substances. 

Develop an improved prediction model that is not driven so heavily by cytotoxicity or, alternatively, which can take better account of cytotoxicity to predict which compounds will elicit dose-limiting maternal toxicity in vivo, and will thus never reach embryotoxic exposures. 

Bhattacherjee. Coir fibre toxicity in vivo and in vitro studies. Toxicol Lett 1982 10(4) 359-365. 

Conjugate was too toxic in vivo to be effective. Succinylation of lysine side chains decreased toxicity, but eliminated anticancer effect against LS180 colon carcinoma... 

The major advantage of an in vitro system is that it represents a simplified system which allows the experimenter to address questions which cannot be tested in vivo. These systems can allow analysis of activation or metabolism at the single enzyme level. They can test proposed pathways of metabolism or activation. Such studies are not practical with in vivo systems. The major disadvantage is that in vitro systems are a simplified system and the results can be easily over-interpreted. In vitro systems cannot model the pharmacokinetics or toxicokinetics of xenobiotic exposure in vivo. In addition, there may be other, unappreciated enzymes or factors which influence metabolism/toxicity in vivo which are not present in the in vitro system. 

Therefore, the data generated from them have to be viewed with caution. This is particularly the case if the data are being used as part of a risk assessment. Such in vitro data may underestimate the toxicity in vivo. 

Although this may seem straightforward, in some cases, the response is only indirectly related and is therefore not a useful parameter of toxicity to use in a dose-response study. This may apply to situations where enzyme inhibition is a basic parameter but where it may not relate to the overall toxic effect. For example, inhibition by lead of aminolaevulinic acid dehydrase, an enzyme, which is involved in heme synthesis, can be readily demonstrated to be dose related, but is clearly not an appropriate indicator of lead-induced renal toxicity in vivo. 

Assay response could lead to prediction of toxicity in vivo which metabolic stability considerations could modify... 

Yan JJ, Cho JY, Kim HS, Kim KL, Jung JS, Huh SO, Suh HW, Kim YH, Song DK. 2001. Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol 133 89-96. 

Hippocampal CuZnSOD mRNA levels are increased after systemic injection of kainate at 7 days after injection. The increased mRNA levels correlated with increased specific activities of the enzyme. The CA1 and CA3 neurons lost their CuZnSOD-like immunoreactivity whereas glial cells showed intense immunoreactivity at 3 and 7 days after KA (Kim et al., 2000a,b). Overexpression of CuZnSOD did not protect against OGD- or kainic-acid-induced toxicity in vivo. On... 

A. Modes of Toxic Action. This includes the consideration, at the fundamental level of organ, cell and molecular function, of all events leading to toxicity in vivo uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Important aspects include the following ... 

Among the alkaloids, the most unusual example is an acaricidal (lethal to arachnids) monot-erpene derivative, altemicidin (Structure 18.3). This novel alkaloid was purified from amarine strain of Streptomyces sioyaensis SA-1758 isolated from marine sediments collected from the northern part of Japan. It yielded potent antitumor activity in vitro against L1210 murine leukemia and IMC carcinoma cell lines, but was toxic in vivo in mice. Altemicidin is a novel sulfur- and nitrogen-containing microbial metabolite with a monoterpene carbon skeleton.12... 

Emeigh Hart SG, Kinter LP (2005) Assessing Renal Effects of Toxicants in vivo. In Tarloff JB, Lash LH (eds) Toxicology of the Kidney, 3rd edn. CRC Press, Boca Raton, pp 81-147 Finco DR (1997) Kidney function. In Kaneko JJ, Harvey JW, Bruss ML (eds) Clinical Biochemistry of Domestic Animals, 6th edn. Academic Press, San Diego, pp 441—485 Futrakul P, Yenrudi S, Futrakul N et al. (1999) Tubular function and tubulointerstitial disease. Am J Kidney Dis 33 886-891... 

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