RIVM - human, liver

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liver


		liver
		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 storage of glycogen and vitamins. Parameter list


		juvenile to adult
		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).

summery of the ontogeny of CYP and some phase II enzymes

enzyme		neonate	infant	child	adult	adult level

CYP1A1	activity	?	?	?	-	?
	mRNA	?	?	?	+
	protein	+	?	?	?
CYP1A2	activity	+/-	+	+++	+++	at 5-6 month
	mRNA	-	+	+++	+++
	protein	-	+	+++	+++
CYP2A6	activity	?	+	++	++	6-13 years
	mRNA	?	+	++	++
	protein	?	+	++	++
CYP2A7	activity	?	?	?	?	?
	mRNA	?	?	?	+
	protein	?	?	?	?
CYP2B(2B6,2B7)	activity	?	++	?	+	higher levels found in infant than adult
	mRNA	?	++	?	+
	protein	?	++	?	+
CYP2C	mRNA	++	++	+++	+++	30% of adult level from 1st week until 1 year
	protein	+	++	+++	+++
CYP2C8	activity	?	?	?	?	?
CYP2C9	activity	+	+	++	++	increasing in 1st week to 50% and adults level not before 1 year
CYP2C18	activity	?	?	?	?	?
CYP2C19	activity	+	+	++	++	9 months
CYP2D6	activity	+/-	+	+	+	?
	mRNA	++	+	+	+
	protein	+/-	+	+	+
CYP2E1	activity	+	+	++	++	protein level after 9 months
	mRNA	+/-	+	++	++
	protein	+	+	++	++
CYP3A4	activity	+/-	++	+++	+++	in the first year replacing CYP3A7
	mRNA	?	++	+++	+++
	protein	?	++	+++	+++
CYP3A5	activity	?	?	?	?	?
	mRNA	+	+	++	++
	protein	+	+	++	++
CYP3A7	activity	++	+	-	-	activity is high in foetus, with a peak in the first week after birth and decrease in first year.
	mRNA	?	?	?	?
	protein	?	?	?	?
UGT1A1	activity	+/-	+	+	+	3-6 months
	mRNA	?	?	?	?
	protein	+/-	+	+	?
UGT1A3	activity	?	?	?	-	?
	mRNA	?	?	?	+
	protein	+	?	?	?
NAT2	activity	+/-	+/-	+	+	10-12 months
	mRNA	?	?	?	?
	protein	?	?	?	?
SULT	activity	+	+	+	+	from birth
	mRNA	?	?	?	?
	protein	?	?	?	?

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

· a foetal group that includes CYP3A7 and CYP4A1, mostly active on endogenous molecules, but also on some exogenous chemicals

· an early neonatal group, which includes CYP2D6 and CYP2E1, that develop quickly during the hours or days after birth

· 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.

Laatste wijziging: 17 december 2007