STRUCTURE-ACTIVITY-RELATIONSHIPS OF CYSTEINE ESTERS AND THEIR EFFECTSON THIOL LEVELS IN RAT LUNG INVITRO

Pretreatment with cysteine esters increases cysteine (CySH) levels in rat lung and protects against the lethal effects of inhaled perfluoroi sobutene in vivo. There are marked differences in the duration of prot ection achieved with different cysteine esters. In this study we have compared the uptake and metabolism of CySH, N-acetyl cysteine (NAc), c ysteine esters and cystine esters in vitro using rat lung and liver ho mogenates and lung slices. Liver homogenates metabolized CySH and cyst eine esters faster than lung homogenates. The half life (T1/2) of CySH in lung was 58.8 +/- 17.3 min and in liver was 14.0 +/- 1.6 min (mean +/- SEM). T1/2 of the esters in lung ranged between 6.5 and 12.1 min and in liver between 1.9 and 5.3 min. Cysteine tertiary butyl ester, w hich does not protect in vivo, was not hydrolysed to CySH by lung or l iver homogenates. All esters increased and prolonged intracellular CyS H concentrations in lung slices to a much greater extent than CySH its elf. NAc did not raise intracellular CySH above that of the controls a nd no NAc appeared within the slice. After CySH incubation intracellul ar CySH was 0.9 +/- 0.1 nmol/mg wet wt at 10 min whereas after incubat ion with the esters it ranged between 2.60 and 3.65 nmol/mg wet wt. Cy steine cyclohexyl ester prolonged the increase of CySH the longest and cysteine methyl ester the shortest. CySH levels with cysteine cyclohe xyl ester were 2.74 +/- 0.15 and 4.13 +/- 0.37 nmol/mg wet wt at 10 an d 60 min, respectively, whereas with cysteine methyl ester, CySH level s were 2.60 +/- 0.5 and 1.25 +/- 0.08 nmol/mg wet wt at similar times. Cystine esters increased intracellular concentrations of both cystine and CySH. CySH concentrations ranged between 2.92 and 3.19 nmol/mg we t wt and cystine between 1.39 and 1.47 nmol/mg wet wt at 60 min. The e levation and duration of CySH in lung slices is well correlated with t he duration of protection against perfluoroisobutene achieved in vivo.