Low-molecular-weight proteins as markers of organ toxicity with special reference to Clara cell protein.

Low-molecular-weight (M(r) between 5 and 40 kDa) proteins present several features related to their small size making them potentially interesting biomarkers of toxicity. They are readily exchangeable and might serve as peripheral indicators of toxic events in relatively inaccessible target organs. They have a short half-life in plasma and may thus respond to both acute and chronic toxic effects. Their catabolism takes place in the proximal tubule which is the segment of nephron which is the most vulnerable to toxic injury. Low-M(r) proteins have been used hitherto in toxicology mainly in relation to their renal handling, i.e. as markers of proximal tubule dysfunction or of glomerular filtration rate, e.g. beta 2-microglobulin (beta 2-m), alpha 1-microglobulin (alpha 1-m) and retinol-binding protein (RBP). The potential of low-M(r) proteins as biomarkers of toxicity might go beyond the field of nephrotoxicity, as suggested by our investigations on a new low-M(r) protein called protein 1 or Clara cell protein (CC16). CC16 is a 16-kDa protein synthesised by non-ciliated cells of the tracheobronchial epithelium, among which the Clara cells which, because of their high xenobiotic-metabolizing activity, are particularly vulnerable to a number of air pollutants. CC16 secreted in the respiratory tract diffuses passively by transsudation into the serum where it may mirror changes occurring in the lung. Recent studies on subjects exposed to lung toxicants (e.g. tobacco smoke and silica) suggest that CC16 in serum or bronchoalveolar lavage fluid is a sensitive marker of bronchial tree injury. CC16 is handled by the kidney as other low-M(r) proteins and may also be used to detect proximal tubule dysfunction. In this respect too, CC16 shows a unique sensitivity and can detect very subtle defects in proximal tubular dysfunction that remain undetected when screening is based on the assay of classical urinary low-M(r) proteins (i.e. beta 2-m, alpha 1-m or RBP).