Introduction

The liver receives blood from the hepatic artery (oxygen) and from the portal vein (compounds absorbed in the gastrointestinal tract). It is the main metabolising organ in the body, but also synthesises bile salts and provides storage of glycogen and vitamins.

Metabolism

The processes of metabolism and disposition have a major bearing upon the biological properties of xenobiotics, determining both the chemical natures and target concentrations of the compound-derived materials in the body. Interspecies differences in metabolism represent a major complication in toxicity testing, being responsible for important differences both in the nature and magnitude of toxic responses. In particular, these differences represent probably the single greatest complicating factor in the use of animal toxicity data as an indication of potential human hazard. The species differences which are encountered in the pathways of xenobiotic metabolism may be qualitative or quantitative in nature. Qualitative differences (see table) may arise from either reactions being restricted in their occurrence to particular species or groups of species or from a species being (relatively) defective in a metabolic reaction of otherwise widespread occurrence (Caldwell, 1992). Some metabolic reactions are restricted to primate species, e.g. aromatisation of quinic acid, glutamine conjugation of arylacetic and aryloxyacetic acids, O-methylation of 4 hydroxy-3,5-diiodobenzoic acid, N-glucuronidation of sulfadimethoxine, C glucuronidation of pyrazolones, quaternisation by glucuronidation of tertiary amines, carbamate acyl glucuronidation (Caldwell, 1986). Quantitative differences arise from differences in activity between the different species.

Table 1: Some examples of species defects for common metabolic reactions (Smith, 1988).‚Äč

Metabolic pathway Substrates affected Species/strain affected Reference
C-oxidation Dibrisoquine and sparteine Rat (DA, female) Al-Dabagh et al., 1981
N-hydroxilation Clorphentermine Rat (Wistar, albino) Caldwell et al., 1975
Expoxide hydration Styrene 7,8-oxide Rat (F344) Oesch et al., 1983
Acetylation Arylamines Dog and related species Bridges and Williams, 1963
Sulphation p-nitrophenol and phenol Mouse (brachymorphic), Pig Capel et al., 1972
Glucuronidation

Bilirubin

Androsteronen and various xenobiotics

Rat (Gunn and other Wistar strains)

Bolivian squirrel monkey

Popper, 1985

Portman et al., 1984

The human liver

In general, within 6-12 months of age metabolism is at adult level. Although some enzyme systems only reach adult levels at 13 years of age. Due to a higher basal metabolic rate in children, the metabolic activity may be even higher in children than in adults. However, whether this results in more, equal or even less sensitivity to xenobiotics in the older infant and child depends on the nature of the compound. It is difficult to generalise about age-dependent deficiencies in the metabolism of xenobiotics because the various enzyme systems mature at different time points. The age at which metabolism is similar to the adult value may be different for each compound. On the other hand, some enzymes are only present during the fetal period and disappear after birth (e.g. CYP3A7).

Table 2: summary of the ontogeny of CYP and some phase II enzymes.

Enzyme Parameter Neonate Infant Child Adult Adult level
CYP1A1

activity

mRNA 

protein

?

?

+

?

?

?

?

?

?

-

+

?
?
CYP1A2

activity

mRNA 

protein

+/-

-

-

+

+

+

+++

+++

+++

+++

+++

+++
5-6 months
CYP2A6

activity

mRNA 

protein

?

?

?

+

+

+

++

++

++

++

++

++
6-13 years
CYP2A7

activity

mRNA 

protein

?

?

?

?

?

?

?

?

?

?

+

?

?
CYP2B6/7

activity

mRNA 

protein

?

?

?

++

++

++

?

?

?

+

+

+

Higher levels found in

infant than adult
CYP2C

mRNA

protein

++

+

++

++

+++

+++

+++

+++

30% of adult level from

1st week until 1 year
CYP2C8 activity ? ? ? ? ?
CYP2C9 activity + + ++ ++

increasing in 1st week to

50% and adult levels

not before 1 year
CYP2C18 activity ? ? ? ? ?
CYP2C19 activity + + ++ ++ 9 months
CYP2D6

activity

mRNA 

protein

+/-

++

+/-

+

+

+

+

+

+

+

+

+
?
CYP2E1

activity

mRNA 

protein

+

+/-

+

+

+

+

++

++

++

++

++

++

Protein levels after

9 months
CYP3A4

activity

mRNA 

protein

+/-

?

?

++

++

++

+++

+++

+++

+++

+++

+++

In the 1st year

replacing CYP3A7
CYP3A5

activity

mRNA 

protein

?

+

+

?

+

+

?

++

++

?

++

++
?
CYP3A7

activity

mRNA 

protein

++

?

?

+

?

?

-

?

?

-

?

?

Activity is high in foetus,

with a peak in 1st week after

birth and decrease in 1st year
UGT1A1

activity

mRNA 

protein

+/-

?

+/-

+

?

+

+

?

+

+

?

+
3-6 months
UGT1A3

activity

mRNA 

protein

?

?

+

?

?

?

?

?

?

-

+

?
?
NAT2

activity

mRNA 

protein

+/-

?

?

+/-

?

?

+

?

?

+

?

?
10-12 months
SULT

activity

mRNA 

protein

+

?

?

+

?

?

+

?

?

+

?

?
From birth

The development of CYP isozymes can be described with three major groups: 

  1. a fetal group that includes CYP3A7 and CYP4A1, mostly active on endogenous molecules, but also on some exogenous chemicals 
  2. an early neonatal group, which includes CYP2D6 and CYP2E1, that develop quickly during the hours or days after birth 
  3. the late neonatal CYPs, which develop later. CYP3A4 and CYP2C rise during the first weeks after birth and CYP1A2 being the last isoform to be expressed in the human liver.