Effect on mitochondrial

At present, direct evidence for the redox control of organellar gene expression, as predicted CORR, is stronger for chloroplasts than for mitochondria (Pfannschmidt et al. 1999). Redox effects on mitochondrial gene expression in vitro are largely confined, at present, to protein synthesis (Allen et al. 1995 Galvis et al. 1998). The search for a direct signalling pathway from the respiratory chain to mitochondrial DNA is likely to be an active area of future research (Allen et al. 2005 Lane 2005). 

Xenobiotics may cause cell death by their effects on mitochondrial DNA Some antiviral dideoxynucleoside... 

Lizasoain, I., Moro, M.A., Knowles, R.G., Darley-Usmar, V., Moncada, S. (1996). Nitric oxide and peroxynitrite exert distinct effects on mitochondrial respiration which are differentially blocked by glutathione or glucose. Biochem. J. 314 877-80. 

No effect on mitochondrial binding or CYPII /I-hydroxylase activity... 

Weinberg, JM, Harding PG, Humes HD, Mechanisms of gentamicin-induced dysfunction of renal cortical mitochondria effects on mitochondrial monovalent cation transport. Arch Biochem Biophys, 1980,205(1) 232-39. 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, and didanosine which has also been attributed to mitochondrial DNA toxicity [95-106]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [91-93,101,105-108]. The link between NRTl effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

Jolly, RA, Ciurlionis R, Morfitt D, et al. Microvesicular steatosis induced by a short chain fatty acid effects on mitochondrial function and correlation with gene expression. Toxicol Pathol. 2004 32(Suppl. 2),19-25. 

The mechanism of citrinin-induced nephrotoxicity has not been completely elucidated. However, it appears that citrinin accumulates in proximal tubular cells via the organic anion transporter, and that the parent compound is the nephrotoxicant species. Mitochondria are early targets for citrinin with multiple effects on mitochondrial function observed following exposure of mitochondria to citrinin, including uncoupling of mitochondrial respiration. The subsequent lost of cellular ATP content may eventually lead to cell death. 

The effects of berbamine on energy metabolism in isolated rat alveolar type II cells (cells which play a critical role in the maintenance of normal lung function) were studied. Incubation of type II cells with berbamine produced a reduction in cellular ATP content, but there was no effect of the alkaloid on cellular oxygen consumption. Berbamine produced an increase in internal calcium levels of type II cells, and incubation of the cells with calcium ionophore, 4-bromo A-23187, led to increased amounts of cellular calcium and reductions in ATP levels, with no effect on oxygen consumption. Exposure of isolated lung mitochondria to calcium produced a concentration-dependent reduction in ATP synthesis with no effect on mitochondrial oxygen... 

Significantly, PGC-la knockout mice also show lesions in the brain regions affected in Alzheimer s disease [106]. It should be noted that TZD agonists of PPARy have a number of effects on mitochondrial metabolism, many of which are receptor-independent actions of the drugs [108]. Roses et al. have postulated that the PPAR agonists act to improve mitochondrial function and... 

Complete elucidation of the mechanisms by which ricin kills target cells remains an area of active study, but it is clear that the A -glycosidase activity of RTA is the essential triggering event. Inhibition of protein synthesis precedes other detectable alterations in target cell biochemistry. Ricin blocks amino acid incorporation in cmde microsome preparations before changes occur in energy metabohsm or oxidative phosphorylation the toxin has essentially no effect on mitochondrial respiration in isolated mitochondria or tumor cells (Waller et al., 1966 Dirheimer et al., 1968 Lin et al., 1971). Likewise, the first observable cytotoxic effect of ricin in cell culture is typically the inhibition of protein synthesis, followed by a reduction in DNA synthesis (Lin et al., 1970 Lin et al., 1971 Onozaki et al., 1972 Refsnes et al., 1974 Nicolson et al., 1975 Olsnes et al., 1976 Refsnes et al., 1977). 

Thyroxine is one of the few hormones for which unequivocal effects on isolated biochemical systems can be observed in particular, it has been shown that thyroxine at high concentrations has a direct effect on mitochondrial oxidation. Tissues from animals which have been injected with thyroid extracts or purified thyroxine show a raised oxygen consumption, particularly in liver and muscle. Similarly the addition of thyroxine to tissue slices of the same organs results in increased oxidation. Thyroxine seems to be especially trapped by the mitochondria, where it stimulates the... 

Gustafsson has reported that Ca " and Mg " have different effects on mitochondrial 26-hydroxylation of endogenous cholesterol, exogenous cholesterol and 5j8-cholestane-3o,7a,12a-triol [132]. He concluded that there might be different transport mechanisms for the two substrates through the mitochondrial membranes. This was later supported by studies by Pedersen et al., showing that the stimulatory effect of Mg was similar for hydroxylation of several substrates catalysed by a partially purified system [133]. 

Toxic and Irritative Effects Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation may follow oral administration of chloramphenicol. Rare toxic effects are blurred vision and digital paresthesias. Tissues with high oxygen consumption e.g., brain, heart) may be particularly susceptible to chloramphenicol s effects on mitochondrial enzymes. 

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