High prevalence of chitotriosidase deficiency in Peruvian Amerindians exposed to chitin-bearing food and enteroparasites.

The human genome encodes a gene for an enzymatically active chitinase (CHIT1) located in a single copy on Chromosome 1, which is highly expressed by activated macrophages and in other cells of the innate immune response. Several dysfunctional mutations are known in CHIT1, including a 24-bp duplication in Exon 10 causing catalytic deficiency. This duplication is a common variant conserved in many human populations, except in West and South Africans. Thus it has been proposed that human migration out of Africa and the consequent reduction of exposure to chitin from environmental factors may have enabled the conservation of dysfunctional mutations in human chitinases. Our data obtained from 85 indigenous Amerindians from Peru, representative of populations characterized by high prevalence of chitin-bearing enteroparasites and intense entomophagy, reveal a very high frequency of the 24-bp duplication (47.06%), and of other single nucleotide polymorphisms which are known to partially affect enzymatic activity (G102S: 42.7% and A442G/V: 25.5%). Our finding is in line with a founder effect, but appears to confute our previous hypothesis of a protective role against parasite infection and sustains the discussion on the redundancy of chitinolytic function.

Differences between human, rat and guinea pig hepatocyte cultures. A comparative study of their rates of beta-oxidation and esterification of palmitate and their sensitivity to R-etomoxir.

Rat hepatocyte cultures have higher rates of beta-oxidation of palmitate and lower rates of esterification to glycerolipid than human or guinea pig hepatocytes. The R-enantiomer of etomoxir (sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), a hypoglycaemic compound and inhibitor of carnitine palmitoyltransferase I, inhibited palmitate beta-oxidation in all three species, but the sensitivity to inhibition was highest in human hepatocytes and lowest in rat hepatocytes. The concentration causing half-maximal inhibition was approximately: 0.1 microM in human; 1 microM in guinea pig and 10 microM in rat hepatocytes. In human and in guinea pig hepatocytes the inhibition of beta-oxidation by R-etomoxir was associated with an increase in the esterification of palmitate but in rat hepatocytes R-etomoxir lowered the total rate of palmitate metabolism. The S-enantiomer of etomoxir had no significant effect on beta-oxidation or esterification of palmitate in any of the three species. It is concluded that there are significant differences between human, rat and guinea pig hepatocytes, not only in the relative partitioning of palmitate between beta-oxidation and esterification, but also in the sensitivity to an inhibitor of carnitine palmitoyltransferase I.

The effects of diphenyleneiodonium on mitochondrial reactions. Relation of binding of diphenylene[125I]iodonium to mitochondria to the extent of inhibition of oxygen uptake.

1. Several ring-substituted derivatives of diphenyleneiodonium catalyse the exchange of Cl- and OH- ions across the inner membrane of rat liver mitochondria. They also inhibit state 3 and state 3u oxidations of glutamate plus malate in the presence of Cl- more than in its absence. Most have activities similar to diphenyleneiodonium, although 2,4-dichlorodiphenyleneiodonium is up to 50 times more active. 2. Diphenyleneiodonium inhibits soluble rat liver NADH dehydrogenase and NADH oxidation by rat liver sub-mitochondrial particles directly; 2,4-dichlorodiphenyleneiodonium is only about twice as inhibitory. 3. Liver mitochondria contain two classes of binding sites for diphenylene[125I]iodonium, namely high-affinity sites with an affinity constant of 3 X 10(5) M-1 (1--2 nmol/mg of protein), and low-affinity sites with an affinity constant of 1.3 X 10(3) M-1 (80 nmol/mg of protein). Both sites occur in hepatocytes with a relative enrichment of the low-affinity site. Nadh dehydrogenase preparations only apparently contain high-affinity binding sites. Only low-affinity sites occur in erythrocytes. 4. 2,4-Dichlorodiphenyleneiodonium competes with diphenylene[125I]iodonium for both low- and high-affinity sites, whereas tri-n-propyltin only competes for the low-affinity sites. 5. The high-affinity sites are apparently associated with NADH dehydrogenase and the low-affinity sites probably represent electrostatic binding of diphenylene[125I]iodonium to phospholipids. The high-affinity site does not appear to be associated with a rate-limiting stage of NADH oxidation.