Clara cytochrome

Inhalation exposure of male B6C3Fi mice to dichloromethane (6 h, once) led to vacuolation of bronchiolar cells at exposure levels > 2000 ppm [6940 mg/m ], while no effect was obsened at levels < 1000 ppm [3470 mg/m (Foster et al., 1994). Pretreatment with the cytochrome P450 inhibitor piperonyl butoxide (300 mg/kg intraperi-toneally) 1 h before the exposure practically abolished the toxic effect upon bronchiolar cells, while buthionine sulfoximine (1 g/kg intraperitoneally), which decreased the pulmonary glutathione content by 50%, had no such protective effect. In Clara cells isolated after exposure to dichloromethane exposure (> 1000 ppm), the proportion of cells in tlie S-phase was increased. 

Certain furan derivatives show selective organ toxicity in animals. One such chemical is 4-ipomeanol (54 see Table 8 for structures), which is toxic to specific cells (Clara cells) in the lungs of treated animals (77MI10501). Administration results in bronchiolar cell necrosis, extensive pulmonary oedema and subsequent death of the animal. Experiments have shown that ipomeanol is localized within the Clara cell (77MI10501), which is considered to be rich in cytochrome P450 (78MI10505), an important enzyme complex for metabolism. The ipomeanol is then converted via the cytochrome P450 into an activated species that alkylates... 

In conclusion, the pulmonary toxicity of 4-ipomeanol seems to be due to metabolic activation of the furan ring, probably by epoxidation, catalysed by the cytochromes P-450 mono-oxygenases found in the Clara cell. The reactive intermediate binds to protein and possibly other macromolecules, initiating cellular necrosis followed by oedema. 

Ipomeanol. This pulmonary toxin is produced by a mould which grows on sweet potatoes. The toxin produces oedema, congestion and haemorrhage resulting from necrosis of the Clara cells (non-ciliated bronchiolar cells). Metabolic activation by a specific form of cytochrome P-450 in these cells produces a reactive metabolite which binds to macromolecules in these cells causing necrosis. Induction and inhibition of cytochrome P-450 may increase and decrease toxicity and depleting GSH increases the toxicity. 

Clara cells have also been shown to have additional functions besides secretion. That is, these cells appear to be prime sites of xenobiotic metabolism in the lung via cytochrome P4go-dependent hydroxylation reactions (Serabjit-Singh et al, I960 Devereaux et al., 1984). Thus, the Clara cells may also be important in the detoxification of inhaled foreign substances. 

Boyd, M. R. Evidence for the Clara cell as a site of cytochrome P450-dependent mixed-function oxidase activity in lung. Nature, 1977, 269, 713-715. 

In mice and rats, but not humans, the smooth endoplasmic reticulum of the Clara cell tends to present as a meshwork of branching tubules and/or vesicles. It is believed to be involved in the detoxification of drugs. Evidence demonstrating that the Clara cell is the primary site of cytochrome P-450 monooxygenase activity within the lung derives from four different approaches ... 

Most experiments with cytochrome P450 and other microsomal enzymes were performed on the Uver. But Clara cells have even higher levels of cytochrome P450 than do the hepatocytes (Serabjit-SiNGH et al. 1980), and are rather selectively injured by number of simple compounds as Usted in Table 21. 

The presence of cytochrome P 450 monooxygenases within Clara cells has been correlated with their susceptibility to metabohcally activated pulmonary cytotoxicants. Species-specific differences in susceptibihty to cytotoxicants exist between Clara cells located in the trachea and bronchi and those in distal bronchioles (Plopper et al. 1992). 

Xenobiotic metaboUsm via cytochrome P-450, which is fourd in relatively high concentration in Clara cells... 

Clara cells are rxinciliated cells in the small bronchioles that contain a relatively high concentration of cytochrome P-450. Therrf, they are equipped to metabolize xenobiolics, and they may bioactivate chemicals to a mote active or mote toxic form. They are often a target for pulmonary toxicants. 

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