Levels in human liver

M. Hosokawa, T. Endo, M. Fujisawa, S. Hara, N. Iwata, Y. Sato, T. Satoh, Interindividual Variation in Carboxylesterase Levels in Human Liver Microsomes , Drug Metab. Dispos. 1995, 23, 1022-1027. 

An appropriate goal is to achieve expression levels for a particular cDNA-derived protein which are comparable to the average level in human liver. However, true parity is not always essential. P450-mediated protoxin activation is usually detectable at lower P450 expression levels, and the unlimited supply of cDNA-derived material allows the utilization of high protein concentrations for metabolite generation. 

Characterization of CYP2B6 protein levels in human liver has been somewhat problematic. Many antibody preparations prepared against rodent CYP2B forms appear to cross-react poorly with the human form. In addition, a CYP2B6-specific or CYP2B6-selective substrate probe has not yet been identified. Therefore, the tools for analysis of human CYP2B6 expression are not fully available. 

M Hosokawa, T Endo, M Fujisawa, S Hara, N Iwata, Y Sato, T Satoh. Interindividual variation in carboxylesterase levels in human liver microsomes. 23(10) 1022—1027, 1995. 

Enzyme Untreated Rat Aroclor-Treated Rat Induction Factor (Rat) Level in Human Liver... 

Hanna, I.H., J.R. Reed, F.R Guengerich, and P.F. Hollenberg (2000). Expression of human cytochrome P450 2B6 in Escherichia coli Characterization of catalytic activity and expression levels in human liver. Arch. Biochem. Biophys. 376, 206-216. 

Maltby J, Wright S, Bird G, Sheron N (1996) Chemokine levels in human liver homogenates associations between GRO alpha and histopathological evidence of alcoholic hepatitis. Hepatology 24 1156-1160... 

Overall, the human intestine is capable of metabolizing UDP-glucuronyltransferase substrates, although the rates of metabolism are between 5- and 10-fold lower than those observed in human liver microsomes. However, the presence of a metabolic capacity towards UDP-glucuronyltransferase substrates at the level of the enterocyte can exert a significant gut wall first-pass extraction on oral administration. 

As can be seen from the results in Table V, fluoride levels in plasma, liver and kidney increased 3 to 8 times but there was no significant effect on the calcium or phosphorus content, although the kidney Ca level in fluoride treated rats was 40 higher than in the controls. Whereas the normal exposure to fluoride from air, food and water did not cause any increase in soft tissue levels, more than ten times the normal levels in soft tissues, including liver and kidney, were found in human fatalities due to fluoride poisoning (15). 

Not present in appreciable levels in human fetal liver. Adult levels reached by approximately 4 months and exceeded in children at 1-2 years of age. Adult activity reached after puberty. Fetal form of CYP3A which is functionally active (and inducible) during gestation. Virtually disappears by 1-4 weeks of postnatal when CYP3A4 activity predominates, but remains present in approximately 5% of individuals. 

Recent evidence confirms that species differences can involve more than one aspect of PPARa-mediated regulation of gene expression. The insensitivity of human liver to rodent peroxisome proliferators is associated with low levels of expression of PPARa in human liver. Marked species differences in the expression of PPARa mRNA have been demonstrated between rodent and human liver, with the latter expressing 1-10% of the levels found in mouse or rat liver (Palmer et al, 1994 Tugwood et al, 1996 Palmer etal, 1998). Using a sensitive and specific immuno/DNA binding assay. Palmer et al (1998) have shown that active PPARa protein is expressed at variable concentrations in human livers. The study compared 20 different human livers and found that those with the highest levels of PPARa protein expression contained less than 10% of the level in mice. Most of the samples (13/20) contained no detectable PPARa activity, but did... 

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