Hepatocytes from rats treated with phenobarbitone were exposed to 10 mM paracetamol for 1 hr and ... more Hepatocytes from rats treated with phenobarbitone were exposed to 10 mM paracetamol for 1 hr and then incubated in buffered Ringer solution. Enzyme leakage and trypan blue entry became severe in the paracetamol treated cells some 2 hr after the end of exposure. These signs of cell injury could be blocked by 4 mM CaEDTA added during or after paracetamol exposure. CaEDTA did not alter covalent binding of [14C]paracetamol. Ca2+ free media did not prevent paracetamol injury. Lipid peroxidation was observed in cells but could be blocked without protecting the cells. Protein synthesis was depressed early on in cells previously exposed to paracetamol, CaEDTA did not protect against this inhibition. These observations suggest that an early cytoplasmic lesion develops into a later lethal lesion at the cell surface.
... McLean and McLean (26) demonstrated that rats fed a protein-free or 3%-protein diet for 4 day... more ... McLean and McLean (26) demonstrated that rats fed a protein-free or 3%-protein diet for 4 days were resistant to the lethal effects of carbon tetrachloride. The LD in control rats was 6.4 ml/kg compared with DU 14.7 ml/kg in rats fed the protein-free diet. ...
A high proportion of toxic and carcinogenic effects of chemicals develop through the pathway of l... more A high proportion of toxic and carcinogenic effects of chemicals develop through the pathway of lethal synthesis. A part of this pathway is along the inducible cytochrome P-450-linked enzyme system. It has previously been suggested that the variations in disease patterns between individuals and between national groups may be due to differences in nutritional intake which in turn act by altering the pathways controlled by cytochrome P-450. However, patients with epilepsy, who are taking large amounts of inducing anticonvulsants, and who are known to have increased cytochrome P-450-linked enzyme activity, fail to show clear-cut changes in their patterns of mortality. It is possible that the reactions in the cytochrome P-450 pathways are not usually rate-limiting steps in toxicity in humans, and that we must look elsewhere, beyond the activation step, for the cause of variability in human responses to toxic materials in the environment. There are in current circulation three major theo...
Short-term in vitro methods (2-6 h) for study of cell injury by paracetamol are often used but, i... more Short-term in vitro methods (2-6 h) for study of cell injury by paracetamol are often used but, in vivo, injury is not apparent until 12 h or later. Many agents which protect in the short-term in vitro systems, such as fructose and glycerol which are effective, even in the late phase, after paracetamol has initiated injury, do not provide any protection in vivo. We have extended the in vitro liver slice system to a more realistic 18 h. Secondly, we have initiated injury with paracetamol in vivo, then followed the progression of injury in an in vitro system. Control liver slices incubated in a HEPES Ringer solution with antibiotics over 18 h show little sign of injury as demonstrated by leakage of lactate dehydrogenase (LDH) into the medium or loss of potassium. Liver slices exposed to 10 mM paracetamol for 2 h in vitro show extensive LDH leak at 6 h which is even more severe at 18 h. Liver slices from animals treated with paracetamol (1 g/kg i.p.) in vivo for 3 h show little LDH leakage at 6 h in vitro but by 18 h injury is very apparent. Fructose and glycerol which protect against paracetamol injury in the short-term (6-h) in vitro system, do not do so when observations are extended to 18 h. They also fail to provide any protection to the slice from animals pre-treated in vivo with paracetamol. Other agents show similar affects. There is no convincing evidence that these short-term protective agents afford any protection in vivo and we show that ibuprofen and dexamethasone do not protect in vivo. It is clear that short-term assays for cell protection have only a limited explanatory value.
Hepatocytes from rats treated with phenobarbitone were exposed to 10 mM paracetamol for 1 hr and ... more Hepatocytes from rats treated with phenobarbitone were exposed to 10 mM paracetamol for 1 hr and then incubated in buffered Ringer solution. Enzyme leakage and trypan blue entry became severe in the paracetamol treated cells some 2 hr after the end of exposure. These signs of cell injury could be blocked by 4 mM CaEDTA added during or after paracetamol exposure. CaEDTA did not alter covalent binding of [14C]paracetamol. Ca2+ free media did not prevent paracetamol injury. Lipid peroxidation was observed in cells but could be blocked without protecting the cells. Protein synthesis was depressed early on in cells previously exposed to paracetamol, CaEDTA did not protect against this inhibition. These observations suggest that an early cytoplasmic lesion develops into a later lethal lesion at the cell surface.
... McLean and McLean (26) demonstrated that rats fed a protein-free or 3%-protein diet for 4 day... more ... McLean and McLean (26) demonstrated that rats fed a protein-free or 3%-protein diet for 4 days were resistant to the lethal effects of carbon tetrachloride. The LD in control rats was 6.4 ml/kg compared with DU 14.7 ml/kg in rats fed the protein-free diet. ...
A high proportion of toxic and carcinogenic effects of chemicals develop through the pathway of l... more A high proportion of toxic and carcinogenic effects of chemicals develop through the pathway of lethal synthesis. A part of this pathway is along the inducible cytochrome P-450-linked enzyme system. It has previously been suggested that the variations in disease patterns between individuals and between national groups may be due to differences in nutritional intake which in turn act by altering the pathways controlled by cytochrome P-450. However, patients with epilepsy, who are taking large amounts of inducing anticonvulsants, and who are known to have increased cytochrome P-450-linked enzyme activity, fail to show clear-cut changes in their patterns of mortality. It is possible that the reactions in the cytochrome P-450 pathways are not usually rate-limiting steps in toxicity in humans, and that we must look elsewhere, beyond the activation step, for the cause of variability in human responses to toxic materials in the environment. There are in current circulation three major theo...
Short-term in vitro methods (2-6 h) for study of cell injury by paracetamol are often used but, i... more Short-term in vitro methods (2-6 h) for study of cell injury by paracetamol are often used but, in vivo, injury is not apparent until 12 h or later. Many agents which protect in the short-term in vitro systems, such as fructose and glycerol which are effective, even in the late phase, after paracetamol has initiated injury, do not provide any protection in vivo. We have extended the in vitro liver slice system to a more realistic 18 h. Secondly, we have initiated injury with paracetamol in vivo, then followed the progression of injury in an in vitro system. Control liver slices incubated in a HEPES Ringer solution with antibiotics over 18 h show little sign of injury as demonstrated by leakage of lactate dehydrogenase (LDH) into the medium or loss of potassium. Liver slices exposed to 10 mM paracetamol for 2 h in vitro show extensive LDH leak at 6 h which is even more severe at 18 h. Liver slices from animals treated with paracetamol (1 g/kg i.p.) in vivo for 3 h show little LDH leakage at 6 h in vitro but by 18 h injury is very apparent. Fructose and glycerol which protect against paracetamol injury in the short-term (6-h) in vitro system, do not do so when observations are extended to 18 h. They also fail to provide any protection to the slice from animals pre-treated in vivo with paracetamol. Other agents show similar affects. There is no convincing evidence that these short-term protective agents afford any protection in vivo and we show that ibuprofen and dexamethasone do not protect in vivo. It is clear that short-term assays for cell protection have only a limited explanatory value.
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Papers by Andre McLean