Biomedical Engineering Reference
In-Depth Information
who had a defective genotype for more than one of these genes were at
greater risk for smoking-induced decline in lung function than those who
had only one defective genotype.
Cytochrome P4501A1:
Cytochrome P4501A1 (CYP1A1) also meta-
bolizes xenobiotic compounds to enabling them to be excreted. Cytochrome
P4501A1 is expressed throughout the lung and may play a role in the activa-
tion of procarcinogens. A polymorphism in exon 7 of CYP1A1 causes an
amino acid substitution (Ile
462
!
Val) that results in increased CYP1A1
activity in vivo (105). The high-activity isoform (Val
462
) was associated with
susceptibility to centriacinar emphysema in patients who had lung cancer
(OR
ΒΌ
2.5) (106).
3. Antioxidants
Heme Oxygenase-1:
Heme oxygenase (HO) degrades heme to bili-
verdin and has been demonstrated to provide cellular protection against
heme and nonheme-mediated oxidant injury (107,108). A polymorphism
consisting of variable numbers of guanine-thymine (GT) nucleotides within
the HO gene (HO-1) promoter was identified. The distribution of the num-
ber of (GT) n repeats was trimodal: short alleles (S:
<
27 GT), middle alleles
(M: 27-32 GT), and long alleles (L:
33 GT) (109). An association study in
a Japanese population found the L allele was associated with pulmonary
emphysema in smokers, yielding an OR of 2.4 (109). The authors hypothe-
sized that the reason for the association was the effect of GT repeats in pro-
moting the formation of a conformation of DNA known as Z DNA. The Z
DNA has been shown to decrease gene expression (110), and therefore a
high number of GT repeats in the HO-1 promoter may suppress expression
of the gene and leave the individual susceptible to oxidant-induced lung
injury. In support of this hypothesis, the authors showed that a high number
of GT repeats resulted in decreased in vitro gene expression in response to
hydrogen peroxide. In a recent study, Hirai et al. (111) reported different
HO-1 mRNA expression level and HO-1 activity between the S
=
S genotype
and the L
=
L genotype, and cell lines with S
=
S genotype were more resistant
to oxidant-induced apoptosis than those with L
=
L genotype, which
provided another possible mechanism for association with susceptibility
to oxidative stress-mediated diseases. However, there was no association
found between HO (GT) n alleles and the rate of decline in lung function
in smokers in a subsequent study of Caucasian individuals (104).
4. Inflammatory Mediators
Vitamin D Binding Protein:
Vitamin D binding protein (VDBP) is a
protein secreted by the liver, which is able to bind vitamin D, extracellular
actin, and endotoxin. Vitamin D Binding Protein enhances the chemotactic
activity of two complement factors (C5a and C5a des-Arg) for neutrophils
by one to two orders of magnitude (112). Chemoattractants, such as these
