3,3,5-trimethylcyclohexan-1-one

Specific investigations: other studies

Administrative data

Endpoint:

chemobiokinetics general studies

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

approx. 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment but no relevant endpoint under REACH

Data source

Reference

Reference Type:

publication

Title:

Cyclohexanol and methylcyclohexanols - a family of inhibitors of hepatic HMGCoA reductase in vivo

Author:

Miciak A, White DA and Middleton B

Year:

1986

Bibliographic source:

Biochem. Pharmacol. 35, 20, 3489-3494

Materials and methods

Principles of method if other than guideline:

QSAR study: Lipid synthesis rate study

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

3,3,5-trimethylcyclohexan-1-one

EC Number:

212-855-9

EC Name:

3,3,5-trimethylcyclohexan-1-one

Cas Number:

873-94-9

Molecular formula:

C9H16O

IUPAC Name:

3,3,5-trimethylcyclohexan-1-one

Details on test material:

Cyclic hydrocarbons with 0-2 alcohol functions, mostly commercial, purities not reported

Test animals

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

- Test organism: male Wistar rats (approx. 230 g)
- Source: Joint Animal Breeding Unit, Nottingham University School of  Agriculture, Sutton Bonington (UK)
- Number of animals: mostly 4/dose group

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

- Administration: 0.5 ml solution in vehicle olive oil;   dose 3 mmol/kg bw by stomach tube, controls; vehicle
- Sacrifice 17 hours later
- Preparation of hepatic microsomes from freshly excised livers
- Assay of HMGCoA reductase activity.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

1 treatment

Frequency of treatment:

1 time

Post exposure period:

17 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
3 mmol/kg
Basis:

No. of animals per sex per dose:

4

Control animals:

yes, concurrent vehicle

Examinations

Examinations:

Lipid synthesis rate study:
- Test organism and administration as above
- 17 hours later i.p. injection of 3H2O
- 1 hour later decaptation, processing of tissues
- Measurement of incorporation of radioactivity into sterol and fatty  acid 
fractions. - Determination of Acetyl CoA carboxylase and alcohol dehydrogenase  activity

Positive control:

no positive control

Results and discussion

Any other information on results incl. tables

- QSAR study: Only monoalcohols were inhibitory:
  cis-3,3,5-trimethylcyclohexanol      61.1 % (p<0.001)
  trans-3,3,5-trimethylcyclohexanol    59.1 % (p<0.01)
  cyclohexanol                         58.3 % (p<0.05)
  1-methylcyclohexanol                 54.9 % (p<0.05)
  3-methylcyclohexanol                 50.6 % (insign.)
  cyclopentanol                        36.8 % (insign.)
  3,3,5-cyclohexanone                  25.0 % (insign.)
  cyclohexane-1,2-diol                 21.5 % (insign.)
  cyclohexane-1,3-diol                 14.6 % (insign.)
  cyclohexane-1,4-diol                 14.5 % (insign.)
  tetrahydropyran                       9.4 % (insign.)
  cyclohexane                           5.0 % (insign.)
- Effect of redox state: When the NADH/NAD ratio was increased by  starvation, 

the effect of cyclohexanols on reductase activity was still  found 

(64 % inhibition by cyclohexanol compared to starved controls,  p<0.05).
- Dose dependence: The inhibition of HMGCoA reductase increased with  

administered dose up to a maximum, which was 70 % at 3 mmol/kg bw in the  

case of 3,3,5-trimethylcyclohexanol.
- Time course: Upon administration of 3 mmol  3,3,5-trimethylcyclohexanol/kg bw 

and sacrifice at various times, enzyme  inhibition began 6-8 hours after 

dosing and was maintained until about 40  hours after dosing.
- Lipid synthesis rate study: 47 % inhibition (P<0.01) of 3H  incorporation 

into digitonin precipitable sterol (DPS) 17 hours after  dosing with 

3,3,5-trimethylcyclohexanol.
- Mechanism: The inhibition of HMGCoA reductase appears to be due to  decreased 

synthesis of HMGCoA reductase in liver following an initial  acute effect in 

the degree of phosphorylation of the enzyme.