Abstract
In our studies on cats with genetic Gm2 gangliosidosis as models for enzyme therapy, we characterized a mechanism responsible for rapid plasma clearance (t½ ∼ 3 min) of human β-hexosaminidase (β-hex)injected into normal cats. Preferential hepatic uptake was shown by recovery studies; circulatory bypass of liver markedly impaired enzyme clearance (t3/2 ∼ 60 min). Carbohydrate-specific uptake, suggested by slow clearance of periodatetreated β-hex (t½ ∼ 60 min) was confirmed by impaired clearance of normal β-hex obtained by injection of terminal N-Acetyl glucosamine- and mannose-rich glycoproteins. Ovomucoid, ovalbumin and ribonuclease-B (final plasma concentration, fpc 0.1, 0.4 and 0.3 mM, resp.) markedly inhibited clearance (t½ ∼ 60 min). Terminal galactose-rich,desialylated orosomucoid and fetuin had no significant effect. Marked inhibition of β-hex clearance (t½ ∼ 60 min) was also obtained by injection of mannose, N-Acetyl glucosamine and L-fucose (fpc 0.15, 0.7, and 0.7M, resp.), but not of glucose or galactose (fpc 0.7M). Thus the feline liver receptor involved in β-hex clearance recognizes terminal mannosyl-and N-Acetyl glucosaminyl-, but not galactosyl residues on glycoproteins. A hepatic receptor with similar specificity, also clearing exogenous lysosomal enzymes, has recently been described in the rat. This suggests that the same mechanism may be present in other mammalian species including man, and may be of critical importance in lysosomal enzyme replacement in humans.
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Rattazzi, M. 556 ENZYME THERAPY IN GM2 GANGLIOSIDOSIS: CARBOHYDRATE-SPECIFIC HUMAN β-HEXOSAMINIDASE UPTAKE BY FELINE LIVER. Pediatr Res 12 (Suppl 4), 456 (1978). https://doi.org/10.1203/00006450-197804001-00561
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DOI: https://doi.org/10.1203/00006450-197804001-00561