Can anyone explain what this means in English please. Is this
permanent?
--- In detox@yahoogroups.com, cherielj@a... wrote:
>
>
> 1: Drug Metab Dispos. 2003 Apr;31(4):384-91. Related
Articles,Links
>
> Inhibition and activation of the human liver microsomal and human
cytochrome
> P450 3A4 metabolism of testosterone by deployment-related
chemicals.
>
> Usmani KA, Rose RL, Hodgson E.
>
> Department of Environmental and Molecular Toxicology, North
Carolina State
> University, Raleigh, NC 27695, USA.
>
> Cytochrome P450 (P450) enzymes are major catalysts involved in the
metabolism
> of xenobiotics and endogenous substrates such as testosterone
(TST). Major
> TST metabolites formed by human liver microsomes include
> 6beta-hydroxytestosterone (6beta-OHTST), 2beta-hydroxytestosterone
(2beta-OHTST), and
> 15beta-hydroxytestosterone (15beta-OHTST). A screen of 16 cDNA-
expressed human P450 isoforms
> demonstrated that 94% of all TST metabolites are produced by
members of the
> CYP3A subfamily with 6beta-OHTST accounting for 86% of all TST
metabolites.
> Similar K(m) values were observed for production of 6beta-, 2beta-
, and
> 15beta-OHTST with human liver microsomes (HLM) and CYP3A4.
However, V(max) and CL(int)
> were significantly higher for 6beta-OHTST than 2beta-OHTST
(approximately
> 18-fold) and 15beta-OHTST (approximately 40-fold). Preincubation
of HLM with a
> variety of ligands, including chemicals used in military
deployments, resulted in
> varying levels of inhibition or activation of TST metabolism. The
greatest
> inhibition of TST metabolism in HLM was following preincubation
with
> organophosphorus compounds, including chlorpyrifos, phorate, and
fonofos, with up to 80%
> inhibition noticed for several metabolites including 6beta-OHTST.
Preincubation
> of CYP3A4 with chlorpyrifos, but not chlorpyrifos-oxon, resulted
in 98%
> inhibition of TST metabolism. Phorate and fonofos also inhibited
the production of
> most primary metabolites of CYP3A4. Kinetic analysis indicated
that
> chlorpyrifos was one of the most potent inhibitors of major TST
metabolites followed by
> fonofos and phorate. Chlorpyrifos, fonofos, and phorate inhibited
major TST
> metabolites noncompetitively and irreversibly. Conversely,
preincubation of
> CYP3A4 with pyridostigmine bromide increased metabolite levels of
6beta-OHTST and
> 2beta-OHTST. Preincubation of human aromatase (CYP19) with the
test chemicals
> had no effect on the production of the endogenous estrogen, 17beta-
estradiol.
>
> PMID: 12642463 [PubMed - indexed for MEDLINE]