Protection by cysteine esters against chemically induced pulmonary oedema.
Perfluoroisobutene (PFIB) is a hydrophobic reactive gas produced by the pyrolysis of polytetrafluoroethane which induces pulmonary oedema similar to that induced by phosgene when inhaled. When a lethal dose is inhaled by Porton strain rats total non-protein thiol (NPSH) and glutathione (GSH) in the lung are reduced by between 30 and 49%, respectively. If the endogenous levels of thiols in the lung are reduced by pretreatment with buthionine sulfoximine (BSO) 16 hr before exposure to PFIB, the rats become more susceptible to the effects of the gas. The effect of BSO pretreatment on toxicity was prevented by pretreatment 30 min before exposure, with 5 mmol/kg N-acetylcysteine (NAc). NAc increased the levels of cysteine (CySH) in the lung by 150% and GSH was unaffected. Similarly pretreatment with 3 mmol/kg CySH also protected against toxicity and raised CySH levels by 100%. A series of cysteine esters and cystine dimethyl ester (CDME) have been synthesised which selectively raise lung levels of CySH in the rat lungs after intraperitoneal (i.p.) injection. The methyl ester and CDME raised lung levels of CySH by 4000 and 2000%, respectively, 10 min after i.p. injection whilst GSH levels remained unchanged. Cysteine isopropyl ester raised lung levels of CySH by 10,600% but liver levels by only 1400%. All esters except the t-butyl ester (CTBE) also raised maximal plasma levels of NPSH by up to 500%; however, when NAc was injected plasma levels increased by over 1500%. Rats treated with these esters at 3 mmol/kg and with NAc at 5 mmol/kg were protected against lethal doses of PFIB in all cases except when CTBE was used. It appears that these cysteine esters may distribute preferentially into the lung, unlike NAc. The selective enhancement of pulmonary CySH levels may provide a method for the protection of lungs against inhaled reactive toxicants by increasing intracellular CySH. Levels of CySH may also be raised in epithelial lining fluid thus reducing access of gaseous toxicants to pulmonary tissue.
Lailey
A F
AF
Biology Division, Chemical and Biological Defence Establishment, Porton Down, Salisbury, Wiltshire, U.K.
Hill
L
L
Lawston
I W
IW
Stanton
D
D
Upshall
D G
DG
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000494:pharmacology; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D005260:Female; D005466:Fluorocarbons / Q000008:administration & dosage / Q000633:toxicity; D005978:Glutathione / Q000032:analysis; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010477:Perfusion; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000097:blood; D013997:Time Factors
D005466:Fluorocarbons; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D003553:Cystine; D019328:Buthionine Sulfoximine; D004247:DNA; D005978:Glutathione; D003545:Cysteine; C017507:mecysteine; C034582:cystine dimethyl ester; D000111:Acetylcysteine