tech: CR alters toxicant dose-response

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Hi All,

It seems that with CR the dose-response to thioacetamide (TA) is different from

the

dose-response in ad lib animals.

See the not yet pdf-available below.

[No authors listed]

Abstracts: 25th Annual Meeting of the American College of Toxicology.

Int J Toxicol. 2004 November-December;23(6):382-401.

PMID: 16040562

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=16040562 & query_hl=6

Dose-Dependent Metabolism of Thioacetamide

J. Chilakapati, M. C. Korrapati, M. S. Mitra, and H. M. Mehendale

Thioacetamide (TA) is bioactivated by CYP2E1 to TA sulfoxide (TASO), and further

to

sulfdioxide, a reactive metabolite that initiates hepatic necrosis by covalent

binding. Dose-response studies showed that liver injury of TA is not

dose-dependent.

Studies have shown that despite higher injury of TA by enhanced bioactivation

due to

approximately 4-fold induction of CYP2E1, diet restriction (DR) protected rats

from

a lethal dose. However, in the DR rats, there was a markedly disproportionate

increase in injury seen after a low dose (50 mg/kg) vs a 12-fold higher dose

(600

mg/kg). The low dose produced a 6-fold higher injury whereas the high dose

produced

only 2.5-fold higher and delayed liver injury compared to ad libitum (AL) fed

rats.

The objective was to determine if lack of dose response for injury in AL and DR

rats

could be explained by TA toxicokinetics. SD rats were kept on 35% DR for 21 days

and

on the 22nd day, both AL and DR rats were given 50 or 600 mg TA/kg ip. TA and

TASO

were quantified in plasma, liver and urine. With increasing doses, the

half-lives of

both TA and TASO increased, revealing that TA bioactivation exhibits zero order

kinetics. Urinary elimination of TASO increased with increasing doses. Covalent

binding of (14)C-TA-derived radiolabel to liver macromolecules was higher after

low

dose compared to high dose. These results explain the lack of dose response for

liver injury. Incubation of TA with microsomes over a concentration range

(0.01-10

mM) showed saturation of TA conversion to TASO at higher concentrations (0.5-10

mM)

which are equivalent to in vivo plasma and liver levels found at highest dose.

DR

rats exhibited lower plasma TA levels at the lethal dose than AL rats. Hepatic

TA

and TASO levels were higher in DR rats at that dose. Low dose showed higher

hepatic

TA and TASO levels, and higher covalent binding in the DR group, explaining

higher

liver injury in DR rats than in AL rats. These findings suggest saturation of

CYP2E1

at the first step (TA to TASO) and substrate inhibition at the second step (TASO

to

TASO(2)) of TA bioactivation as evidenced by decreased covalent binding at the

lethal dose than at the low dose. Also, despite higher CYP2E1 in DR, zero order

kinetics of TA bioactivation prevents a linear dose related increase in liver

injury.

Al Pater, PhD; email: old542000@...

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